1. Genes as genetic candidates in ADHD with a plausible pathway to ADHD

• ADHD candidate genes with a plausible pathway in relation to ADHD
• Dopamine
  • Dopamine synthesis
    • 1.8. DDC, AADC, aromatic L-amino acid decarboxylase (chromosome 9q34.2)
    • 1.9. TH, tyrosine hydroxylase (chromosome 11p15.5)
    • 1.121. AS3MT, arsenite methyltransferase
    • FAH, fumarylacetoacetate hydrolase
  • Dopamine storage and release
    • 1.28. SNAP25, Synaptosome Associated Protein 25 (chromosome 20p12.3; T1065G)
    • 1.275. SYT1, Synaptotagmin 1
    • 2.99. DNM1, Dynamin 1
  • Dopamine effect
    • 1.1. DRD1, dopamine receptor D1 (chromosome 5q35.2)
    • 1.2. DRD2, dopamine receptor D2 (chromosome 11q23.1; TAQ1A, rs1800497)
    • 1.3. DRD3, dopamine receptor D3 (chromosome 3q13.31)
    • 1.4. DRD4, dopamine receptor D4 (chromosome 11p15.5 exon III, VTNR) (x)
    • 1.5. DRD5, dopamine receptor D5 (chromosome 4p16.1-p15.3; CARepeat, 148 bp)
    • 1.234. ADORA2A, ADENOSINE A2A RECEPTOR
    • 1.109. PPP2R2B, Protein Phosphatase 2 Regulatory Subunit B beta
  • Dopamine degradation
    • Dopamine reuptake
      • 1.6. SLC6A3, DAT1, dopamine transporter gene (chromosome 5p15.3; 10-R allele, VNTR)
      • 1.18. SLC6A2, NET, noradrenaline transporter gene (chromosome 16q12.2)
      • 1.97. CACNA1C, Calcium Voltage-Gated Channel Subunit Alpha1 C
      • 1.98. CACNB2, Calcium Voltage-Gated Channel Auxiliary Subunit Beta 2
      • 1.105. MAN2A2, mannosidase alpha class 2A member 2
      • 2.104. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A
    • 1.93. TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD
    • Dopamine metabolization
      • 1.10. MAOA, monoamine oxidase A gene (chromosome Xp11.3) (x)
      • 1.11. MAOB, monoamine oxidase B gene (chromosome Xp11.4-p11.3)
      • 1.12. COMT, catechol-O-methyltransferase (chromosome 22q11.21)
        • 1.12.1. COMT Val158Val
        • 1.12.2. COMT Met158Met
        • 1.12.3. COMT Val108/158 Met
      • 1.283. STS, STEROID SULFATASE
  • Dopamine regulation
    • 1.31. DRD1IP, calcylon (chromosome 10q26) (x)
    • 1.78. MTHFR, 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE
    • 1.81. ARTN, Artemin; 1p34.1
    • 1.127. GPR139, Probable G-protein coupled receptor 139
    • 1.279. FOXP2
    • 1.303. NR4A2, NURR1, Nuclear Receptor Subfamily 4 Group A Member 2
    • 1.122. CSMD1, CUB And Sushi Multiple Domains 1
  • Potassium channels influence dopamine
    • 1.85. KCNJ6, Potassium Inwardly Rectifying Channel Subfamily J Member 6
    • 1.67. DPP10, dipeptidyl peptidase like 10 (chromosome 2q14.1)
    • 1.268. KCNC2, Potassium Voltage-Gated Channel Subfamily C Member 2
    • 1.100. DPP6, dipeptidyl-aminopeptidase-like protein 6
    • 1.64. KCNC1 (chromosome 11p15.1)
    • 1.65. KCNIP4, Potassium Voltage-Gated Channel Interacting Protein 4 (chromosome 4p15.3-p15.2)
    • 1.66. KCNIP1, Potassium Voltage-Gated Channel Interacting Protein 1
    • 1.256. ALG10, ALG10 alpha-1,2-glucosyltransferase
  • Other dopaminergic influences
    • 1.30. ADGRL3, LPHN3, latrophilin-3 (chromosome 4q13.1)
    • 1.296. SORCS3, Sortilin Related VPS10 Domain Containing Receptor 3
    • 1.76. DIRAS2; DIRAS FAMILY, GTP-BINDING RAS-LIKE PROTEIN 2 (chromosome 9q22.2)
    • 1.90. TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1
    • 1.125. FERMT3, FERM Domain Containing Kindlin 3
    • 1.82. GLI1; PPD1; GLI Family Zinc Finger 1
    • 1.307. DGKH; Diacylglycerol Kinase Eta
    • 1.101. EMP2, Epithelial Membrane Protein 2
    • 1.317. SYN3, Synapsin III
    • 1.318. SYN1, Synapsin 1
• Noradrenaline
  • Noradrenaline synthesis
    • 1.7. DBH, dopamine beta-hydroxylase (chromosome 9q34.2; Taql A)
  • Noradrenaline effect
    • 1.46. ADRA1A, ALPHA-1A-ADRENERGIC RECEPTOR (chromosome 8p21.2)
    • 1.17. ADRA2A, ALPHA-2A-ADRENERGIC RECEPTOR (chromosome 10q25.2)
    • 1.69. ADRA2C, ALPHA-2C-ADRENERGIC RECEPTOR (chromosome 4p16.3)
    • 1.44. ADRB2, BETA-2-ADRENERGIC RECEPTOR (chromosome 5q32)
  • Noradrenaline reduction
    • Noradrenaline reuptake
      • 1.18. NET, noradrenaline transporter gene (chromosome 16q12.2)
    • Development of the noradrenaline system
      • 1.329. MECP2
• Serotonin
  • Serotonin synthesis
    • 1.16. Tryptophan hydroxylase gene (chromosome 11p15.1)
    • 1.77. TPH1, tryptophan hydroxylase 1 gene (chromosome 11p15.1)
    • 1.21. TPH2, tryptophan hydroxylase 2 gene (chromosome 12q21.1)
  • Serotonin effect
    • 1.13. HTR1B, serotonin receptor 1B (chromosome 6q14.1)
    • 1.51. HTR1E, serotonin receptor 1E (chromosome 6q14.3)
    • 1.14. HTR2A, serotonin receptor 2A (chromosome 13q14.2)
  • Serotonin degradation
    • Serotonin reuptake
      • 1.15. SLC6A4, serotonin transporter gene, 5-HTT gene (chromosome 17q11.2)(x)
    • Serotonin metabolization
      • 1.20. Tryptophan 2,3-dioxynase (chromosome 4q32.1)
• Steroids
  • 1.19. Androgen receptor (chromosome Xq11-q12)
• GABA
  • 1.162. SLC6A12, GABA transporter
  • 1.319. SLC6A1, GABA transporter
  • 1.22. GABA receptor alpha3 (chromosome Xq28)
  • 1.23. GABA receptor beta-3 (chromosome 15q11.2-q.12)
  • 1.35. CDH13, Cadherin13 (chromosome 16q23.3)
  • 1.116. KIF21B, Kinesin Family Member 21B
• Acetylcholine
• Acetylcholine effect
  • 1.32. CHRNA7, alpha-7 neuronal nicotinic acetylcholine receptor
  • 1.50. CHRNA4, alpha-4-neuronal nicotinic acetylcholine receptor (chromosome 20q13.33)
  • 1.212. LYPD1, LY6/PLAUR Domain Containing 1
• Choline depletion
  • 1.40. SLC5A7, CHT1, CHOLINE TRANSPORTER
  • 1.237. SLC44A1, Solute Carrier Family 44 Member 1
• Glutamate
  • 1.39. GRM1, glutamate receptor metabotropic 1 (chromosome 6p24-3)
  • 1.225. GRIK3, Glutamate Ionotropic Receptor Kainate Type Subunit 3
  • 1.312. GRIK1, Glutamate Ionotropic Receptor Kainate Type Subunit 1
  • 1.34. GRM5, glutamate receptor metabotropic 5 (chromosome 11q14..2 - 14.3) (33, p. 55)
  • 1.38. GRM7, glutamate receptor metabotropic 7 (chromosome 3p26.1)
  • 1.43. SLC9A9, Solute Carrier Family 9 Member A9 (chromosome 3q24)
• Cannabinoids
  • 1.37. CNR1, cannaboid receptor 1 (chromosome 6q14-q15)
• Traceamine
  • 1.42. PNMT, phenylethanolamine, N-methyltransferase (chromosome 17q12)
• Glycine
  • 1.89. SLC6A9, glycine transporter
• Nitric oxide
  • 1.36. NOS1, nitric oxide synthase 1 (chromosome 12q24.22) (87)
• Neurotransmitter storage and release
  • 1.114. CPLX2, Complexin 2
  • 1.177. STXBP6, Syntaxin Binding Protein 6
  • 1.242. MYO5B, Myosin VB
  • 1.263. TRAPPC11, Trafficking Protein Particle Complex Subunit 11
• Brain development
  • 1.33. NDE1, Nuclear distribution gene E homologue 1
  • 1.106. MAP1B, Microtubule Associated Protein 1B
  • 1.107. MOBP, Myelin-Associated Oligodendrocyte Basic Protein
  • 1.56. ASTN2, ASTROTACTIN 2 (chromosome 9q33.1)
  • 1.110. TCF4, Transcription Factor 4
  • 1.111. TLL2, Tolloid Like 2
  • 1.117. TENM4, Teneurin Transmembrane Protein 4
  • 1.91. ANK3, ANKYRIN 3
  • 1.120. ANKS1B, Ankyrin Repeat And Sterile Alpha Motif Domain Containing 1B
  • 1.233. EPHA7, EPH Receptor A7
  • 1.299. SEMA6D, Semaphorin 6D
  • 1.63. NAV2, NEURON NAVIGATOR 2 (chromosome 11p15.1)
  • 1.119. CNNM2, Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2
  • 1.324. DLG4 / PSD-95
  • 1.325. FEZ1
• Growth factors, neurogenesis
  • 1.25. NTF3, neurotrophin 3 (chromosome 12p13.31)
  • 1.71. NTF4, NEUROTROPHIN 4 (chromosome 19q13.33)
  • 1.26. BDNF, brain-derived neurothropic factor (chromosome 11p14.1) (X)
  • 1.27. BAIAP2, Brain-specific angiogenesis inhibitor 1-associated protein
  • 1.70. NGF, NERVE GROWTH FACTOR (chromosome 1p13.2)
  • 1.72. GDNF, GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR (chromosome 5p13.2)
  • 1.54. UNC5, C. ELEGANS, HOMOLOG OF, B; UNC5B (chromosome 10q22.1)
  • 1.61. GPC6, GLYPICAN 6 (chromosome 13q31.3-q32.1)
  • 1.232. CNTN5, Contactin 5
• Cell development
  • 1.298. POC1B, POC1 Centriolar Protein B
  • 1.62. CTNNA2, CATENIN ALPHA-2 (chromosome 2p12)
• Circadian rhythm
  • 1.29. CLOCK, Clock Circadian Regulator (chromosome 4q12) (x)
  • 1.261. PER1, Period Circadian Regulator 1 (chromosome 2q37.3)
  • 1.47. PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2 (chromosome 2q37.3)
  • 1.73. VASOACTIVE INTESTINAL PEPTIDE RECEPTOR 2; VIPR2 (chromosome 7q36.3)
  • 1.79. KAT2B, LYSINE ACETYLTRANSFERASE 2B
  • 1.84. CADM1, CELL ADHESION MOLECULE 1 (TSLC1, IGSF4); CADM2, ELL ADHESION MOLECULE 2
  • CRY1
• Immune system
  • 1.57. CSMD2, CUB AND SUSHI MULTIPLE DOMAINS 2 (chromosome 1p35.1)
  • 1.112. TRIM26, Tripartite Motif Containing 26
  • 1.210. MYO1G, Myosin IG
  • 1.230. TLR4, Toll Like Receptor 4
• Stress systems
  • HPA axis
    • 1.74. NR3C1, Nuclear Receptor Subfamily 3 Group C Member 1, glucocorticoid receptor (chromosome: 5q31.3)
    • 1.75. FKBP5, FK506-BINDING PROTEIN 5 (chromosome 6p21.31)
    • 1.60. CDH23, CADHERIN 23 (chromosome 10q22.1)
    • 1.254. NAT2, N-acetyltransferase 2
  • Oxidative stress
    • 1.297. DUSP6, Dual Specificity Phosphatase 6
  • Further consequences of stress
    • 1.108. NCL, Nucleolin
• Broadly effective mechanisms
  • Transcription
    • 1.95. RERE
    • 1.45. HES1; HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 1 (chromosome 3q29)
    • 1.86. FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1
    • 1.143. ZNF763, Zinc Finger Protein 763
    • 1.134. ZNF615, Zinc Finger Protein 615
    • 1.139. POLR1H, RNA polymerase I subunit H
  • Receptor activity
    • 1.41. ARRB2, arrestin beta 2 gene (chromosome 17p13.2)
  • Neurotransmitter storage
    • 1.49. SYP, SYNAPTOPHYSIN (chromosome Xp11.23)
  • Purine metabolism
    • 1.115. NT5C2, 5’-nucleotidase, Cytosolic II
  • Adhesion
    • 1.288. PCDH7, protocadherin 7
    • 1.53. SPATA13, SPERMATOGENESIS-ASSOCIATED PROTEIN 13 (chromosome 13q12.12)
    • 1.58. ITGAE, integrin subunit alpha E (chromosome 17p3.2)
    • 1.59. ITGA11, integrin subunit alpha 11 (chromosome 15q23)
• Cerebral damage
  • 1.287. SPAG16, Sperm Associated Antigen 16

ADHD candidate genes with a plausible pathway in relation to ADHD¶

Dopamine¶

Dopamine synthesis¶

1.8. DDC, AADC, aromatic L-amino acid decarboxylase (chromosome 9q34.2)¶

Other names: DOPA decaboxylase

OMIM: DOPA decaboxylase gene, DDC

DDC is a candidate gene for ADHD.¹
DDC deficiency increases the likelihood of ADHD symptoms.²

The DDC gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.039.³

One study found reduced striatal and prefrontal dopa decarboxylase activity in children with hyperactivity (but not in adults).⁴

1.9. TH, tyrosine hydroxylase (chromosome 11p15.5)¶

Other names: Tyrosine 3-monooxygenase; DYT5b; Tyrosine 3-hydroxylase; EC 1.14.16.2; TYH; Dystonia 14; EC 1.14.16; DYT14

The protein TH catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa), the rate-limiting step in the biosynthesis of cathecolamines, dopamine, noradrenaline and adrenaline. TH uses tetrahydrobiopterin and molecular oxygen to convert tyrosine into L-dopa. In addition to tyrosine, TH can also catalyze the hydroxylation of phenylalanine and tryptophan with less specificity. TH positively regulates the regression of retinal hyaloid vessels during postnatal development. Isoform 5 and isoform 6 show no catalytic activity.⁵
TH is associated with

• Segawa syndrome, autosomal recessive
• Dystonia

Related signal paths:

• dopaminergic neurogenesis
• Metabolism of amine-based hormones
• Enzyme binding
• Oxygen binding

Paralog: PAH

Tyrosine hydroxylase is a candidate gene for ADHD.¹

1.121. AS3MT, arsenite methyltransferase¶

Other names: CYT19, S-Adenosyl-L-Methionine:Arsenic(III) Methyltransferase, Arsenic (+3 Oxidation State) Methyltransferase, Methylarsonite Methyltransferase, S-Adenosylmethionine:Arsenic (III) Methyltransferase, Methyltransferase Cyt19, EC 2.1.1.137

The protein AS3MT plays a role in arsenic metabolism. AS3MT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to trivalent arsenic, resulting in methylated and dimethylated arsenic compounds. AS3MT methylates arsenite to methylarsonate, Me-AsO(3)H(2), which is reduced to methylarsonite, Me-As(OH)2, by methylarsonate reductase. Methylarsonite is also a substrate and is converted into the much less toxic compound dimethylarsinate (cacodylate), Me(2)As(O)-OH.

AS3MT is associated with

• Borst-Jadassohn Intraepidermal carcinoma
• ADHD
• Epilepsy⁶

AS3MT rs7085104 is associated with a change in striatal dopamine synthesis capacity.⁶

One study found AS3MT to be one of the 51 most likely gene candidates for ADHD.⁷

FAH, fumarylacetoacetate hydrolase¶

Other names: Fumarylacetoacetase; Beta-Diketonase; EC 3.7.1.2; FAA; Fumarylacetoacetate Hydrolase (Fumarylacetoacetase); Epididymis Secretory Sperm Binding Protein; FUMARYLACETOACETATE HYDROLASE

FAH encodes a protein that enables fumarylacetoacetase activity. It appears to be involved in L-phenylalanine catabolism, homogentisate catabolism and tyrosine catabolism. E appears to be active upstream of or within the arginine degradation process. FAH is located in the extracellular exosome.⁸
FAH is associated with

• Tyrosinemia type I (HT1, TT-1)

Paralog: FAHD2B.

Tyrosinemia (here: hereditary tyrosinemia type 1, HT-1 or TT-1), a rare disorder of tyrosine degradation that leads to increased tyrosine levels, is associated with increased inattention.⁹¹⁰

Dopamine storage and release¶

1.28. SNAP25, Synaptosome Associated Protein 25 (chromosome 20p12.3; T1065G)¶

Other names: SNAP-25; DJ1068F16.2; BA416N4.2; RIC-4; RIC4; SEC9; SNAP; Resistance To Inhibitors Of Cholinesterase 4 Homolog; Synaptosomal-Associated Protein, 25kDa; Synaptosomal-Associated Protein 25; SUP; Synaptosomal-Associated 25 KDa Protein; Synaptosome Associated Protein 25kDa; Super Protein; CMS1

The SNARE protein SNAP-25 mediates - together with syntaxin-1 and synaptobrevin - the release of neurotransmitters from synaptic vesicles in neurons.
SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) mediate the docking and fusion of synaptic vesicle membranes located at the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is delivered by v-SNARE and the other three by t-SNARE. For the t-SNAREs on the plasma membrane, the protein syntaxin provides one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. SNAP25 regulates plasma membrane recycling through its interaction with CENPF. SNAP25 odulates the gating properties of the voltage-gated delayed rectification potassium channel KCNB1 in pancreatic beta cells.¹¹
SNAP25 is associated with

• Myasthenic syndrome, congenital, 18
• Developmental and epileptic encephalopathy

Related signal paths:

• Neurotransmitter release cycle
• wtCFTR and delta508-CFTR traffic / Generic scheme (standard and CF)
• Calcium-dependent protein binding
• SNAP receptor activity

Paralog: SNAP23

OMIM: 25-kD synaptosomal-associated protein gene / SYNAPTOSOMAL-ASSOCIATED PROTEIN, 25-KD; SNAP25

SNAP25 is a candidate gene for ADHD.¹¹² SNAP25 was identified as a candidate gene for ADHD in a 2006 study with p = 0.035.³

1.275. SYT1, Synaptotagmin 1¶

Other names: P65; Synaptotagmin I; SVP65; SYT; Synaptotagmin-1; SytI; BAGOS

Synaptotagmins are integral membrane proteins of synaptic vesicles that are thought to serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. The binding of calcium to synaptotagmin-1 is involved in triggering neurotransmitter release at the synapse.
SYT1 is a calcium sensor involved in triggering neurotransmitter release at the synapse. SYT1 may regulate membrane interactions during the transport of synaptic vesicles in the active zone of the synapse. SYT1 binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. There appears to be a Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C. SYT1 plays a role in melanocyte dendrite formation. SYT1 can bind to at least three other proteins in a Ca(2+)-independent manner:¹³

• Neurexin
• Syntaxin
• AP2

While Syt7 (synaptotagmin7), a high-affinity Ca2+ sensor, underlies phasic somatodendritic dopamine release and its Ca2+ sensitivity in the substantia nigra pars compacta, SYT1 underlies axonal dopamine release as a Ca2+ sensor and plays a role in tonic, but not phasic, somatodendritic dopamine release. However, SYT1 can facilitate phasic dopamine release when SYT7 is deactivated. SYT1 and SYT7 act as Ca2+ sensors that support different aspects of somatodendritic dopamine release.¹⁴

SYT1 is associated with:

• Baker-Gordon syndrome
• Syndromic Intellectual Disability

Related signal paths:

• Neurotransmitter release cycle
• Calcium ion binding
• Transporter activity

Paralog: SYT2

SYT1 was identified as a candidate gene for ADHD in a 2008 study. It is said to correlate with general ADHD symptoms.¹⁵

2.99. DNM1, Dynamin 1¶

Other names: DNM, EC 3.6.5.5, Dynamin-1, EIEE31, DEE31

The DNM1 protein is a member of the dynamin subfamily of GTP-binding proteins. DNM1 has unique mechanochemical properties that are used to tubulate and disrupt membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble, resulting in stimulation of GTPase activity.¹⁶
Connected signal paths:

• Integrin pathway
• Development of the nervous system.

Mutations in DNM1 are associated with

• Autism¹⁷
• epileptic encephalopathy¹⁸
  • infantile spasms with onset between 2 and 13 months
  • later development of Lennox-Gastaut syndrome
  • severe to profound mental disability
  • pronounced hypotension
  • missing language.

Most pathogenic variants are missense variants that have been shown to impair the endocytosis of synaptic vesicles In a dominant-negative manner.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

Dopamine effect¶

1.1. DRD1, dopamine receptor D1 (chromosome 5q35.2)¶

OMIM: Dopamine receptor D1 gene, DRD1

DRD1 is a candidate gene for ADHD.¹

The DRD1 receptor is closely related to the DRD5 receptor, but is found in other brain regions, namely in the striatum, nucleus accumbens, olfactory tubercle and frontal cortex - i.e. in brain regions where barely any DRD1 receptors are found.¹⁹

1.2. DRD2, dopamine receptor D2 (chromosome 11q23.1; TAQ1A, rs1800497)¶

OMIM: Dopamine receptor D2 gene, DRD2
DRD2 is a candidate gene for ADHD.¹

The A allele has been associated with a lower receptor density in the striatum in several studies. This means that existing dopamine can be absorbed to a lesser extent, which has the same effect as a reduced dopamine level.²⁰
The DRD2-A1 allele is said to correlate with impulsivity, compulsiveness and addiction²¹

One study found a significantly increased ADHD and ASD risk overlap in correlation with the DRD2-12 (rs7131465) gene polymorphism.²²

The DRD2 gene variants rs6277 and rs6275 correlated significantly with ADHD in boys and girls, respectively. In addition, a significant correlation was found between DRD2 rs6275 and SCLA6A3 (DAT1) rs1012586. It is possible that the interaction between the GRIN2B and DRD2 genes contributes to the susceptibility of Chinese children to ADHD.²³

1.3. DRD3, dopamine receptor D3 (chromosome 3q13.31)¶

OMIM: Dopamine receptor D3 gene, DRD3
DRD3 is a candidate gene for ADHD.¹

In mice, the D3 receptor was found to have an effect on increased motor activity (hyperactivity) and rearing behavior. Binding of the D3 receptor prevents addictive behavior (craving).

1.4. DRD4, dopamine receptor D4 (chromosome 11p15.5 exon III, VTNR) (x)¶

OMIM: Dopamine receptor D4 gene, DRD4

DRD4 is a candidate gene for ADHD.^2412125
DRD4 was identified as a candidate gene for ADHD in a 2006 study with p = 0.055.³
The DRD4-7R variant increases the risk of ADHD by 50% (odds ratio 1.5).²⁶
The 7-repeat allele encodes the dopamine receptor D4 in such a way that it requires 3 times the amount of dopamine to respond. ²⁷²⁸ This has the effect of seemingly reducing dopamine levels in the striatum, which correlates with motivational problems and impulsivity²⁹
In other words, DRD4-7R causes reduced postsynaptic inhibition.³⁰³¹
A recent report suggests that DRD4-7R is not simply less sensitive to dopamine, but rather interacts with other dopamine receptors. In addition, DRD4, like all D2-type receptors (D2, D3 and D4), is also said to react to noradrenaline as an agonist.³²

DRD4-7R increases the reactivity of the ventral striatum.
DRD4-7R therefore does not cause a lower dopamine level in the striatum per se, but reduces the inhibition of the striatum by only reacting inhibitively to higher dopamine levels.
Surprisingly, however, DRD4-7R also has an inhibitory effect on a methamphetamine-induced increase in dopamine and glutamate in the striatum. A methamphetamine-induced increase in dopamine and glutamate was reduced in mice with the DRD4-7R gene.³³ In contrast, cocaine did not show a reduced increase in dopamine or glutamate in DRD4-7R. The increase in dopamine on cocaine was significant in all DRD4 variants, while the increase in glutamate was rather low.
Striatal glutamate stimulates the increase in dopamine in the striatum.³³
Adenosine modulates striatal DA release by stimulating glutamate release at adenosine receptors in the striatum, which increases dopamine levels.³⁴
DRD4-7R causes reduced function and connectivity of brain regions involved in inhibitory control during the execution of impulse control tasks, in particular the right inferior frontal gyrus cortex.³³³⁵³⁶
Flattened corticostriatal neurotransmission impairs GABAergic activity in the striatum during “Go” and “NoGo” tasks and reduces the ability to increase reactivity to reward-related stimuli and suppress reactivity to non-reward-related or aversive stimuli.³⁷
This increases the “interest” in irrelevant stimuli and reduces the inhibition of irrelevant responses, as shown in distractibility and action and decision impulsivity in ADHD.³³ This contradicts representations that DRD4-7R is associated with the ADHD-I subtype.

We hypothesize that DRD4-7R is linked to increased impulsivity, which is more typical of the ADHD-HI subtype.
DRD4-7R is associated with novelty seeking.⁴³ Novelty seeking correlates with high impulsivity.
A cohort study found that DRD4-7R generally correlated with high levels of hyperactivity/impulsivity.⁴⁴
DRD4-7R causes less formation of gyri and sulci (gyrification) in the PFC of people with ADHD.⁴⁵

DRD4-7R is only around 40,000 to 50,000 years old and has since spread far faster than would be expected from random gene transmission. This indicates that DRD4-7R is an extremely successful gene.³¹⁴⁶

DRD4-4R and DRD4-7R appear to strongly and differently influence the functionality of the D2-short receptor variant.⁴⁷

The DRD4 variants Dup 120bp and VNTR 48bp variants are involved in the etiology of adult ADHD. A gene-environment analysis showed an independent effect of stress experience on the severity of ADHD persisting into adulthood and a gene-environment interaction in relation to inattention, with non-carriers of the Dup 120bp (L) - VNTR 48bp (7R) haplotype being more sensitive to environmental stress than carriers.⁴⁸

A review on the epigenetic causation of ADHD points to the relevance of DRD4.⁴⁹

1.5. DRD5, dopamine receptor D5 (chromosome 4p16.1-p15.3; CARepeat, 148 bp)¶

OMIM: Dopamine receptor D5 gene, DRD5

DRD5 is a candidate gene for ADHD.¹²¹

The DRD5 receptor is closely related to the DRD1 receptor, but is found in other (primarily limbic) brain regions, namely the hippocampus, mamillary nuclei, anterior pretectal nuclei, and all brain regions in which barely any DRD1 receptors are found.¹⁹
DRD5 is widely distributed in the brain and has a significantly higher affinity for dopamine than the D1 receptor. The DRD5-148 bp allele in 18.5 kb at the end of the 5′-flank is associated with ADHD.⁵⁰
DRD5 appears to moderate the hypothalamus and parts of motor control.⁵¹

1.234. ADORA2A, ADENOSINE A2A RECEPTOR¶

Other names: ADORA2; RDC8; Adenosine Receptor A2a; Adenosine Receptor Subtype A2a; A2aR

OMIM: ADENOSINE A2A RECEPTOR; ADORA2A

The protein ADORA2 is the adenosine A2a receptor. ADORA2 is a member of the guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) superfamily, which is subdivided into classes and subtypes. The receptors are seven-pass transmembrane proteins that respond to extracellular stimuli and activate intracellular signal transduction pathways. ADORA2 uses adenosine as its preferred endogenous agonist and preferentially interacts with the G(s) and G(olf) family of G-proteins to increase intracellular cAMP levels. It plays an important role in many biological functions such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation and sleep. A2A receptors are highly expressed in the spleen, thymus, leukocytes, platelets and olfactory bulb.⁵²
ADORA2 is associated with

• Acute encephalopathy with biphasic seizures and late reduced diffusion
• Basal ganglion disease
• Inflammatory diseases
• neurodegenerative disorders

Paralog: ADORA2B

A possible significant association between the A2AAR gene polymorphism rs35320474 and ADHD has been reported.⁵³
Another study reported a correlation between rs5751876 TC in children with ADHD and rs2298383 CC in children with ADHD-HI, but this was no longer significant after Bonferroni correction.⁵⁴

Adenosine is very closely linked to the effect of dopamine. Adenosine A2A receptors and dopamine receptors form receptor heterodimers. Adenosine inhibits dopamine via the A2A receptor. More on this under Adenosine.

1.109. PPP2R2B, Protein Phosphatase 2 Regulatory Subunit B beta¶

Other names: PR55-BETA, PR52B, Serine/Threonine-Protein Phosphatase 2A 55 KDa Regulatory Subunit B Beta Isoform, PP2A Subunit B Isoform Beta, B55beta, SCA12, Protein Phosphatase 2 (Formerly 2A), Regulatory Subunit B (PR 52), Beta Isoform, Protein Phosphatase 2, Regulatory Subunit B, Beta, PP2A Subunit B Isoform PR55-Beta, PP2A Subunit B Isoform B55-Beta

The protein PPP2R2B belongs to the family of protein ser/threonine phosphatases. These are a group of enzymes that catalyze the removal of phosphate groups from serine and/or threonine residues by hydrolysis of phosphoric acid monoesters. They counteract the action of kinases and phosphorylases, are involved in signal transduction and in the inhibition of cell growth and division.
PPP2R2B modulates substrate selectivity and catalytic activity as well as the localization of the catalytic enzyme in a specific subcellular compartment. Isoform 2 is required for the promotion of proapoptotic activity and regulates neuronal survival by balancing mitochondrial fission and fusion.⁵⁵

PPP2R2B is associated with

• autosomal dominant spinocerebellar ataxia 12 (SCA12; degeneration of the cerebellum and sometimes of the brain stem and spinal cord; poor coordination of speech and body movements)
• autosomal dominant cerebellar ataxia

PPP2R2B and dopamine:
The signaling effect of dopamine receptors is not limited to the regulation of cAMP production. Some receptors can couple to GαQ-G proteins to regulate intracellular inositol and calcium signaling. Further, activation of Gβγ-G protein subunits by DRD2 leads to neuronal hyperpolarization by regulating the activity of L- and N-type calcium channels (LTCC and NTCC) and of G protein-gated inwardly rectifying potassium channels (e.g. GIRK2/KCNJ6).⁵⁶ In addition, DRD2 modulates neuronal function by acting on G-protein-independent mechanisms. Once activated, dopamine receptors are phosphorylated by G-protein receptor kinases (e.g. GRK2, GRK6). This leads to the recruitment of beta-arrestins (ARBB1 and ARBB2), which inactivate G-protein coupling, stimulate internalization of the receptor and mediate further cell signalling functions. In the case of DRD2, the recruitment of ARBB2 leads to the formation of a protein complex that favors the inactivation of Akt family protein kinases (AKT1, AKT2, AKT3) by protein phosphatase 2 holoenzymes (i.e. PPP2R2B, PPP2CA, PPP2CB). The inactivation of AKT kinases downstream of DRD2 triggers the inhibition of glycogen kinase 3 family proteins (GSK3A, GSK3B), thus increasing their activity.⁵⁷

A SNP associated with the expression of PPP2R2B (rs959627) appears to predict prefrontal activity during the N-back working memory task.
The allele rs959627T correlated with:⁵⁸

• reduced PPP2R2B expression in the PFC
• increased activity in the right inferior frontal gyrus (IFG) during N-Back
• poorer behavioral performance with N-Back
• reduced efficiency of the right IFG during working memory processing

One study found PPP2R2B to be one of the 51 most likely gene candidates for ADHD.⁷ Another study found PPP2R2B rs9325032 to be the gene most strongly associated with ADHD⁵⁹

Dopamine degradation¶

Dopamine reuptake¶

1.6. SLC6A3, DAT1, dopamine transporter gene (chromosome 5p15.3; 10-R allele, VNTR)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3

OMIM: SLC6A3 (DAT1) SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3;

The dopamine transporter (DAT), which plays the main role in dopamine reuptake, is mainly found in the striatum⁶⁰ and only slightly in the PFC.

To illustrate the diversity of gene variants, we cite the 73 DAT1 gene variants without known disease association identified by Mergy et al in 2014: K3N; M11I; M11V; S12P; V14M; A16T; P17L; E20(stop); E20V; I32M; V24A; G39R; L42F; P50L; S53R; V73; L104I; G121S; V131I; L138P; L138R; A161T; A163V; A192T; S198T; S202L; S202W; G209R; V221M; R237W; V245A; I268V; T271N; V275L; L281P; G289R; G293S; V300I; E307K; A308V; A314V; D345G; A346T; A346V; F362L; L368Q; Q373R; G380R; P395L; G433R; D436N; R445G; A455V; V464I; V471I; I490V; V501A; Q509H; R515W; S517T; G538A; V538I; R544S; P545T; H547Q; A559T; A576E; K579R; R588Q; G607W; R610H; T613M; K619N.⁶¹

The DAT1 gene, which encodes the DAT, is often cited as an ADHD candidate gene.^{2412 1 25 3} in particular the DAT1 variant 10/10⁶²
A certain DAT1 variant is said to be primarily associated with the ADHD-HI subtype.³⁸ The binding of the DAT is associated with motor hyperactivity, but not with inattention.²⁴ In the ADHD-HI subtype (with hyperactivity), the striatum is primarily affected. The caudate nucleus is conspicuously reduced in size.⁶³
A certain DAT1 gene variant causes an excessive number of dopamine transporters. An excessive number of dopamine transporters causes the dopamine released presynaptically (by the sending neuron) to be taken up again by the excess DAT like a vacuum cleaner by the presynapse (the sending neuron) before it can be taken up postsynaptically (by the receiving neuron). The correctly released amount of dopamine therefore does not reach the postsynaptic dopamine receptors, which is why they do not receive the required amount of decision information (which would only be triggered if a sufficient number of receptors had received dopamine).³⁹⁶⁴
The relevant polymorphisms of the DAT gene occur significantly more frequently in families of people with ADHD (n = 329). A combination of 3 specific polymorphisms is associated with a 2.5-fold higher frequency of ADHD.⁶⁵
Certain DAT1 variants cause a predisposition to lower birth weight and ADHD susceptibility.⁶⁶
DAT Val559 - unlike the DAT Ala559 variant - is said to be associated with increased dopamine transport capacity, which could be relevant in ADHD, autism and bipolar disorder.⁶⁷
The DAT variant Ala559Val (hDAT A559V) is thought to cause increased dopamine efflux as triggered by amphetamine. Tonic activation of DRD2 supports hDAT A559V-mediated increased dopamine efflux. hDAT A559V has a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports DRD2-driven dopamine efflux.⁶⁸ Ala559Val (hDAT A559V) showed:⁶⁹

hDAT VAL559 also shows increased dopamine efflux and is associated with ADHD, ASD and BPD. KOR antagonists reduced the increased dopamine release in VAL559 in vivo. Similarly, hDAT VAL559 increased DAT-Thr53 phosphorylation and normalized DAT trafficking. Conversely, wild-type KOR agonists increased DAT-Thr53 phosphorylation and DAT trafficking.⁷⁰

The DAT1 gene variant 12P572A shows an increased DAT efflux with less dependence on ion or dopamine concentrations.⁷¹
The SLC6A3 gene variant rs2652511 correlated significantly with ADHD in boys and girls, respectively. In addition, a significant correlation was found between DRD2 rs6275 and SCLA6A3 (DAT1) rs1012586.²³
The DAT1 rs27048 (C)rs429699 (T) haplotype was associated with altered functional connectivity of the left dorsal caudate nucleus in visual memory performance of adolescents with ADHD in a study.⁷²

Rare coding DAT polymorphisms were found in persons with ADHD and bipolar disorder.

• Val24Met⁷³
• Val55⁷⁴
  • Val55A shows
  • increased dopamine km
  • reduced cocaine affinity
• Leu167Phe⁷³
• Arg237⁷⁴
• Val382⁷⁴
  • Ala substitutions in the extracellular loop 4, which stabilizes the extracellular gate
  • reduced dopamine affinity
  • increased cocaine affinity
  • changed PKC-dependent regulation
• DAT-Asp421Asn⁷⁵
  • showed almost no dopamine uptake
  • Computer simulations and uptake experiments suggest impaired sodium binding as the cause of the dysfunction
  • constitutive, abnormal dopamine efflux
  • large cation leak that could further disrupt dopaminergic neurotransmission
• Ala559⁷⁴
  • Val substitutions at the extracellular end of TM12 have been found in persons with ADHD, bipolar disorder and autism⁷⁶
  • A559V⁶⁹
    • very rare gene variant
    • tripled dopamine efflux, with depolarized cell potentials
      • at the level triggered by AMP in normal DAT
    • MPH and AMP both blocked Ala559Val-mediated dopamine efflux
      • in wild-type HDAT, MPH and AMP increase this
    • increased sensitivity to intracellular Na+, but not to intracellular dopamine
    • possibly increased basal hDAT A559V phosphorylation, which is attenuated by AMP
    • normal DAT protein and cell surface expression
    • normal dopamine (re)uptake⁷⁷ at both low and high dopamine levels
    • normal effect of AMP, MPH, cocaine on dopamine reuptake inhibition
    • an older A559V carrier showed
      • high hyperactivity/restlessness
      • high impulsivity/emotional susceptibility
      • high hyperactive-impulsive symptom scores according to DSM-IV (over 90)
    • increased efflux is CaMK-dependent and is mediated by DRD2⁷⁶
      • indicates the involvement of endogenous signaling and phosphorylation mechanisms
    • Increased PKCβ activity⁷⁶
    • releases DA by fusion of synaptic vesicles triggered by afferent electrical stimulation, followed by efficient DAT-mediated DA uptake that inactivates DA signaling
• Val559⁷⁸⁷⁰
  • comparable total and cell surface DAT protein expression to Ala559
  • dA transport kinetics comparable to Ala559
  • abnormal DA efflux
    • abnormal, DAT-mediated, outward “leakage” of cytoplasmic DA when cells are preloaded with DA
    • voltage-dependent; DA efflux more pronounced with depolarized membrane potentials
    • DA efflux in parallel with vesicular DA release
      • causes loss of tight coupling of DA release to the afferent input
      • even a single Val559-encoding transporter can increase DA efflux and ADHD risk
    • AMP increases intracellular Na+, which supports DA efflux⁷⁹
    • AMP could not induce DA efflux in DAT Val559-transfected cells, but only acted as a DAT antagonist and blocked DA efflux
    • Treatment with psychostimulants
      • reduces DA clearance by blocking DAT reduces
      • prevents DA efflux at the same time
      • restores an overall more normal relationship between DA neuron activity and extracellular DA levels
• Glu602⁷⁴
• Arg615Cys⁸⁰⁷⁴
  • in C-terminal CaMK binding site
  • Cys substitution of this residue causes numerous regulatory changes associated with a chronically downregulated DAT, including:
    • increased transporter phosphorylation
    • reduced Flot1 binding
    • reduced membrane raft distribution
    • endocytosis induced by PKC or AMP is reduced
  • dAT levels at the cell surface reduced by 50
  • correspondingly reduced DA transport speed
  • Shift in surface distribution from regulated to constitutive recycling
  • increased association with calcium/calmodulin-dependent protein kinase II (CaMKII)
  • impaired localization in GM1 ganglioside-enriched membrane microdomains.

Other rare DAT gene variants that are not associated with ADHD:

• I312F⁷⁷
  • rare DAT1 gene variant
  • impaired dopamine uptake with changes in ligand binding, ion coordination and significant conformational disorders
  • mediated an increased uncoupled anion conductivity
  • DAT-Ile312Phe
    • showed significantly reduced dopamine uptake capacity
    • retained diaphragm alignment
    • both indicate impaired catalytic activity
    • Computer simulations and uptake experiments suggest that the impaired function of the DAT-Asp421Asn mutant is due to impaired sodium binding, consistent with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive abnormal efflux of dopamine, and electrophysiological analysis revealed a large cation leak that could further disrupt dopaminergic neurotransmission
• T356M
  • rare DAT1 gene variant
  • cocaine-sensitive release of cations, enhanced by Zn2+
  • reduced dopamine reuptake⁷⁷
    • DAT expression in the striatum unchanged
    • Vmax of the resumption reduced
    • consequences of reduced resumption are
      • D2R desensitization
      • reduced dopamine synthesis due to increased synaptic dopamine levels
      • reduced total content of dopamine in the tissue
      • reduced tyrosine hydroxylase phosphorylation at Ser31
      • synaptic hyperdopaminergia
      • increased striatal dopamine metabolism
  • permanent DA efflux⁸¹
  • reduced DAT affinity for cocaine and MPH (suggesting an important role of T356 in inhibitor binding)⁷⁷
    • DA peak release on cocaine as with wild type
    • Decay time of amperometric current in DAT T356M+/+ mice significantly longer than in wild type, corresponding to reduced reuptake
  • reduced body weight
  • plays a role in ASD
  • only T356M+/+, not T356M+/- mice show behavioral peculiarities compared to wild type
    • spontaneous hyperactivity persistent
      • reduced by DAT antagonists
        • ACT-01: within 20 minutes
        • GBR12909: within 10 minutes
    • repetitive behaviors
    • social deficits
      • Loss of preference for new social encounters
      • Loss of social dominance
    • Loss of motivated behavior or altered choice of action (reduced burying of marbles)
  • unchanged:
    • Power
    • Coordination
    • motor learning
    • Anxiety
    • Stress behavior
• D421N⁷⁷
  • rare DAT1 gene variant
  • impaired dopamine uptake with changes in ligand binding, ion coordination and significant conformational disorders
  • cocaine-sensitive leakage of cations, not enhanced by Zn2+
• E602G⁷⁷
  • rare DAT1 gene variant
  • Recovery unchanged compared to wild type
• R615C⁷⁷
  • rare DAT1 gene variant
  • Recovery unchanged compared to wild type
• DAT1 gene variant Asn336 (ΔN336)⁸²
  • hDAT mutation
  • associated with ASD in humans
  • reduced dopamine uptake (non-existent)
  • Dopamine efflux reduced to approx. 1/3
  • in Drosophila:
    • impaired social behavior during the flight
    • Hyperactivity
    • prolonged freezing and a reduced willingness to flee in response to predatory signals
    • increased anxiety
• T62D-hDAT⁸³⁸⁴
  • DAT expression reduced
  • drastically reduced dopamine uptake (by 50 %)
  • higher basal dopamine efflux
  • Zn(2+) at micromolar concentrations significantly potentiated dopamine uptake in T62D-hDAT and enabled the measurement of amphetamine-stimulated dopamine efflux.

1.18. SLC6A2, NET, noradrenaline transporter gene (chromosome 16q12.2)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, NORADRENALINE), MEMBER 2

OMIM: Noradrenaline transporter gene, SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, NORADRENALINE), MEMBER 2; SLC6A2, NET

SLC6A2 is a candidate gene for ADHD.¹⁸⁵

The NET gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.012.³

Children with ADHD with the SLC6A2 rs36011 (T) / rs1566652 (G) haplotype showed abnormalities in the intrinsic brain activity of the sensorimotor and dorsal attention networks, which correlated with impairments in visual memory and visual attention.⁸⁶

NET1-rs3785143 is thought to be associated with increased emotional lability in ADHD.⁸⁷

1.97. CACNA1C, Calcium Voltage-Gated Channel Subunit Alpha1 C¶

Other names: CACH2, CACN2, CACNL1A1, CCHL1A1, LQT8, TS, Calcium Channel, Voltage-Dependent, L Type, Alpha 1C Subunit

Pore-forming alpha-1C subunit of the voltage-gated calcium channel that elicits L-type calcium currents. Mediates the influx of calcium ions into the cytoplasm and thereby triggers the release of calcium from the sarcoplasm. Important for excitation-contraction coupling in the heart. Required for normal heart development and normal heart rhythm regulation. Required for normal contraction of smooth muscle cells in blood vessels and the intestine. Essential for normal blood pressure regulation through its role in the contraction of arterial smooth muscle cells.⁸⁸
Acts as a receptor for influenza viruses. CACNA1C may be relevant for enabling virus entry when sialylated and expressed on lung tissue
CACNA1C is associated with clinical diagnoses of:⁸⁹

• bipolar Disorder
• Depression
• Schizophrenia

CACNA1C encodes the L-type calcium channel (LTCC) Cav1.2 LTCCs are required for normal dopaminergic neurotransmission between the VTA and nucleus accumbens. Reduced CACNA1C levels attenuate the function of the mesolimbic dopamine system: in mice with CACNA1C haploinsufficiency, sub-second frequency dopamine release was insensitive to DAT inhibition. Constitutive CACNA1C haploinsufficiency caused reduced hypermotor activity after acute administration of DAT-specific stimulants. Locomotor sensitization of these mice to the DAT antagonist GBR12909 was weaker than in wild-type mice. Sensitization to GBR12909 was selectively attenuated in the VTA but not in the nucleus accumbens in mice with reduced CACNA1C. CACNA1C appears to modify the presynaptic function of the mesolimbic dopamine system. Since the identified single nucleotide polymorphisms are found in an intronic (non-protein coding, “in intron”) region of CACNA1C, the genetic risk influence is likely to occur via altered CACNA1C levels in certain brain regions.⁸⁹ Hyperlmotor activity induced by high doses of d-amphetamine is attenuated in mice lacking one copy of CACNA1C .⁹⁰

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.98. CACNB2, Calcium Voltage-Gated Channel Auxiliary Subunit Beta 2¶

Other names: CACNLB2, MYSB, Voltage-Dependent L-Type Calcium Channel Subunit Beta-2, Calcium Channel, Voltage-Dependent, Beta 2 Subunit

CACNB2 mediates the entry of calcium ions into cells. CACNB2 contributes to calcium channel function by increasing the peak calcium current, shifting the voltage dependence of activation and inactivation, modulating G-protein inhibition and controlling membrane targeting of the alpha-1 subunit.⁹¹
CACNB2 is associated with:⁹²⁹³

• High blood pressure
  • rs4373814-G/C35
  • rs12258967-G/C46
  • rs11014166-A/T81
• bipolar Disorder
• Brugada syndrome 4
• major depressive disorder
• Schizophrenia
• Lambert-Eaton myasthenia syndrome
• Autism Spectrum Disorder
• ADHD
• Heart failure
• sudden cardiac death

Related signal paths:

• sensory processing of sound
• CREB signal path

Stimulation of L-type calcium channels increases tyrosine hydroxylase And dopamine in ventral midbrain cells.⁹⁴ In addition, there are several other indications that L-type calcium channels influence the dopamine balance.^95969798

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷
Mutations in the CACNB2 gene have also been associated with ADHD:⁹⁹

1.105. MAN2A2, mannosidase alpha class 2A member 2¶

Other names: MANA2X; Mannosyl-Oligosaccharides 1,3-1,6-Alpha-Mannosidase; Alpha-Mannosidase IIx; Alpha-Mannosidase 2x; EC 3.2.1.114; Alpha-Mannosidase II, Member 1

The MAN2A2 protein enables alpha-mannosidase activity. It is involved in N-glycan processing, by catalyzing the first step in the biosynthesis of complex N-glycans. MAN2A2 is thus involved in protein deglycosylation. It is probably an integrative component of the membrane and active in the Golgi membrane.
Glycosylases are a group of enzymes that includes glucosidases, mannosidases and heparanases. There are two glucosidase subtypes (MAN2A1 and MAN2A2), both of which are found in the intestine. They hydrolyze terminal (1,4)-alpha-glucoside bonds and (1,6)-beta-glucoside bonds, releasing alpha-glucose and beta-glucose.¹⁰⁰ MAN2A2 - like MAN2A2 - is expressed at a relatively high level, presumably because it is required for complex N-glycans¹⁰¹
MAN2A2 is associated with

• abdominal obesity - metabolic syndrome Quantitative Trait Locus 2
• Schizophrenia (not clear)¹⁰¹

MAN2A1-KO mice show a deficiency of N-glycans on erythroid cells, anemia and a late-onset autoimmune disease similar to systemic lupus erythematosus, but otherwise no disorders.
MAN2A2-KO mice show male infertility without other disorders.
Deletion of either MAN2A1 or MAN2A2 alone leads to relatively mild and organ-specific phenotypes.
Deletion of MAN2A1 and MAN2A2 together causes perinatal lethality and complete deficiency of complex N-glycans¹⁰¹

One study found MAN2A2 to be one of the 51 most likely gene candidates for ADHD.[^7]

2.104. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A¶

Other names: STT3-A, TMC, Integral Membrane Protein 1, ITM1, Dolichyl-Diphosphooligosaccharide-Protein Glycosyltransferase Subunit STT3A, STT3A, Catalytic Subunit Of The Oligosaccharyltransferase Complex, Dolichyl-Diphosphooligosaccharide Protein Glycotransferase, Oligosaccharyl Transferase Subunit STT3A, Transmembrane Protein TMC

The protein STT3A is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex, which transfers glycan chains to asparagine residues of target proteins in the endoplasmic reticulum. It is associated with CFTR activation by S-nitrosoglutathione (normal and CF) and the translation of structural proteins.
STT3A is associated with

• congenital disorder of glycosylation, type Iw, autosomal recessive
• congenital disorder of glycosylation, type Iw, autosomal dominant

In view of the influence of STT3A on N-glycolysis, we assume that the pathway of action on the dopaminergic system is comparable to that of 1.105. MAN2A2.

One study found STT3A to be one of the 51 most likely gene candidates for ADHD.⁷

1.93. TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD¶

Other names: TAFII250, DYT3/TAF1, NSCL2, TAF2A, KAT4, BA2R, CCG1, CCGS, TAF1 RNA Polymerase II, TATA Box Binding Protein (TBP)-Associated Factor, 250kDa, Transcription Initiation Factor TFIID Subunit 1, TBP-Associated Factor 250 KDa, Cell Cycle Gene 1 Protein, EC 2.7.11.1, TAF(II)250

TAF1 plays a special role in the expression of the dopamine transporter. In contrast to most housekeeping genes, the DAT promoter lacks a TATA box. As a result, the initiation of DAT transcription may be highly dependent on the composition of the TATA box-binding protein (TBP), which is primarily regulated by histone acetylation. This unique genomic structure makes DAT susceptible to epigenetic regulation¹⁰⁵

The TAF1 protein:

• is the largest subunit and the core scaffold of the basal transcription factor complex TFIID.
• contains new N- and C-terminal Ser/Thr kinase domains that can autophosphorylate or transphosphorylate other transcription factors
• phosphorylates TP53 at ‘Thr-55’, which leads to MDM2-mediated degradation of TP53
• phosphorylates GTF2A1 and GTF2F1 at Ser residues
• has DNA-binding activity
• essential for the progression of the G1 phase of the cell cycle
• shows histone acetyltransferase activity towards histones H3 and H4
• binds to core promoter sequences that encompass the transcription start site
• binds to activators and other transcriptional regulators, which influences the speed of transcription initiation
• contains two independent protein kinase domains at the N- and C-terminus
• has acetyltransferase activity
• can act as a ubiquitin-activating/conjugating enzyme.
• controls apoptotic pathways in synovial fibroblasts

Mutations of TAF1 lead to

• Dystonia 3, torsion, X-linked, a dystonia-parkinsonism disorder
• Intellectual development disorder, X-linked, syndrome 33

OMIM: TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD

A study found a change in the expression of TAF1 in ADHD.¹⁰⁶

Dopamine metabolization¶

1.10. MAOA, monoamine oxidase A gene (chromosome Xp11.3) (x)¶

OMIM: Monoamine oxidase A gene, MAOA

MAO-A is a candidate gene for ADHD.¹

The MAO-A gene controls the formation of the enzyme monoamine oxidase-A. The MAO-A gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.02.³
A certain variant of the MAO-A gene doubles the risk of aggression and antisocial behavior if the person with ADHD was exposed to violence (or let’s say more generally: intense stress) in their childhood. It occurs more frequently in boys, as men - unlike women - do not have a second copy of this gene that could mitigate the defect.
This MAO-A gene variant is also associated with ADHD. However, we consider this to be a comorbidity that often occurs together with ADHD-HI (not ADHD-I) and not a part of ADHD. So does Steinhausen regarding Disorders of Social Behavior,¹⁰⁷ which is the most common comorbidity. However, Steinhausen describes the comorbidity of Disorders of Social Behavior as a subtype of ADHD, which we do not share due to the separability of the remaining genetic basis. Another argument in favor of pure comorbidity and against an ADHD-HI subtype is that drugs for aggression disorders and antisocial behavior are typically dopamine D2 receptor antagonists (antipsychotic drugs), which reduce the effect of dopamine uptake at the postsynaptic neuron at the (inhibitory*) D2 receptor, whereas in ADHD it is assumed that the receptor affinity is too low (see above).

1.11. MAOB, monoamine oxidase B gene (chromosome Xp11.4-p11.3)¶

MAO-B is a candidate gene for ADHD.¹

In contrast to MAO-A inhibitors, MAO-B inhibitors proved to be ineffective in ADHD.¹⁰⁸

1.12. COMT, catechol-O-methyltransferase (chromosome 22q11.21)¶

OMIM: Catechol-O-methyltransferase; COMT

COMT is a candidate gene for ADHD.¹

1.12.1. COMT Val158Val¶

The COMT gene variant Val158Val causes an increased breakdown of dopamine and noradrenaline and thus leads to a dopamine deficiency in the PFC, which in turn, however, can cause increased dopaminergic activity in the mesolimbic system.^{109110 111 112} .¹¹³

1.12.2. COMT Met158Met¶

The COMT Met158 Met variant correlates with antisocial behavior in ADHD.¹¹⁴

This could explain why this gene variant in ADHD is only observed in comorbid antisocial behavior, but to our knowledge not in ADHD in general. In addition, this gene variant is associated with borderline and (via the increased dopaminergic activity of the mesolimbic system) the positive symptoms of schizophrenia.
This gene variant directly impairs working memory, which in turn indirectly controls delay aversion and directly controls executive functions and attention control, as well as, together with the latter, the processing of acoustic stimuli, which is a prerequisite for language processing. There are more contradictory than confirmatory studies on the question of whether this COMT gene variant correlates with ADHD, although these did not take working memory into account.¹¹⁵
This gene variant is further relevant in antisocial behavior disorder associated with ADHD, but not in ADHD without antisocial behavior disorder.¹¹⁰ In our understanding, however, antisocial behavior disorder is a comorbid disorder and not part of ADHD.

1.12.3. COMT Val108/158 Met¶

The COMT Val108/158 Met polymorphism reduces the activity of the enzyme in the degradation of dopamine to a quarter. This variant correlates with a more focused and efficient cerebrovascular response in working memory tasks. ¹¹⁶
This variant is not associated with ADHD, in which dopamine levels are too low, but with schizophrenia, in which dopamine levels in the synaptic cleft are elevated.

1.283. STS, STEROID SULFATASE¶

Steroid sulfatase causes the breakdown of dopamine by sulfation. More on this under Sulfation by sulfotransferases In the article Dopamine degradation.

The STS gene is a candidate ADHD gene.¹¹⁷¹¹⁸

Dopamine regulation¶

1.31. DRD1IP, calcylon (chromosome 10q26) (x)¶

Other names: DOPAMINE RECEPTOR D1-INTERACTING PROTEIN

Calcylone is involved in the regulation of the D1 receptor.¹¹⁹

OMIM: Calcyon (CALY) gene / DOPAMINE RECEPTOR D1-INTERACTING PROTEIN; DRD1IP gene

CALY / DRD1IP is a candidate gene for ADHD.¹

1.78. MTHFR, 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE¶

The enzyme methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylene-FH4 with the help of NAD(P)H to 5-methyl-FH4. As this produces the methylating agent 5-methyl-FH4, MTHFR is indispensable in many metabolic pathways, including the breakdown of harmful homocysteine to methionine, and in bacterial methane formation.
Humans express MTHFR in many tissue types, from where the protein is released into the blood. Variants and mutations of the MTHFR gene can lead to reduced or, more rarely, increased MTHFR synthesis and efficacy. MTHFR deficiency can

• in pregnant women can be the cause of neural tube malformations such as spina bifida in newborns
• Trigger homocystinuria
• Increase the risk of stroke
• Increase the risk of bowel cancer.

Homocysteine reduces the dopamine level in the striatum.¹²⁰

OMIM: MTHFR (5,10-METHYLENETETRAHYDROFOLATE REDUCTASE)

The 1298A > C polymorphism of the MTHFR gene was associated with an increased risk of ADHD, but not the MTHFR 677 C > T polymorphism.¹²¹

The MTHFR 1298A > C polymorphism is associated with increased homocysteine levels, probably due to reduced degradation of homocysteine by this polymorphism.¹²²

ADHD correlates with increased homocysteine levels (and decreased vitamin B12 levels).¹²³¹²⁴
B12 deficiency can increase homopcysteine levels.¹²⁵

1.81. ARTN, Artemin; 1p34.1¶

ARTN (artemin, enovin, neublastin) is a neurotrophic factor of the glial cell line-derived neurotrophic factor ligand family, a group of ligands within the TGF-beta superfamily of signaling molecules. ARTN promotes the survival of a number of peripheral neuron populations and at least one population of dopaminergic CNS neurons. ARTN frequently expresses near these neurons. ARTN is a ligand for the RET receptor and utilizes GFR-alpha 3 as a coreceptor. ARTN plays a role in axonal development.
ARTN is involved in the structural development and plasticity of various types of neurons, including the dopaminergic neurons of the ventral mesencephalon. ARTN plays an important role in the migration, proliferation and differentiation of sympathetic neurons during development.

OMIM: ARTN, Artemin; 1p34.1

Increased expression and decreased methylation in ADHD.¹²⁶
Candidate gene in a GWAS study.¹²⁷

1.127. GPR139, Probable G-protein coupled receptor 139¶

Other names: G(q)-coupled orphan receptor GPRg1, G-protein-coupled receptor PGR3

GPR139 is active in the plasma membrane. GPR139 is involved in G protein-coupled receptor signaling (particularly Gq/11 and somewhat less so G12/13), phospholipase C-activating G protein-coupled receptor signaling and signal transduction. GPR139 may play a role in motor activity, food intake, alcohol dependence and hyperalgesia and phenylketonuria (PKU)
Endogenous agonists are probably the aromatic amino acids L-Trp and L-Phe as well as ACTH/α-MSH-related peptides. GPR139 appears to increase cAMP and induce an ERK phosphorylation reaction.
GPR139 appears to form receptor heterodimers with the dopamine D2 receptor and to moderate D2 activation.¹²⁸

The GPR139 receptor is expressed almost exclusively in the brain, particularly in the ventrolateral region of the putamen caudatus, the nucleus habenularis, the zona incerta and the nucleus mammillaris medialis,¹²⁹ according to another source in the striatum, thalamus, hypothalamus, the pituitary gland and the habenula of the CNS.¹²⁸

GPR139 appears to be associated with:¹²⁸

• Schizophrenia
• ADHD and inattention symptoms
• Depression
• fetal development

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.279. FOXP2¶

A substitution of two amino acids (T303N, N325S) in the transcription factor FOXP2 in mice showed reduced dopamine levels in these mice:¹³⁰

• Nucleus accumbens
• Frontal cortex
• Cerebellum
• Putamen caudatus
• Globus pallidus

A meta-analysis of GWAS studies (k = 12, n = 55,374) found FOXP2 associated with ADHD.¹³¹ This is consistent with the result from one (n = 1,262) of two study arms of a previous study¹³²
FOXP2 is further associated with a severe speech disorder.¹³³ FOXP2 is subsequently implicated in the development of corticostriatal and olivocerebellar circuits involved in motor control.

1.303. NR4A2, NURR1, Nuclear Receptor Subfamily 4 Group A Member 2¶

Other names: TINUR; NOT; HZF-3; RNR1; Transcriptionally-Inducible Nuclear Receptor; Immediate-Early Response Protein NOT; Orphan Nuclear Receptor NURR1; Transcriptionally Inducible Nuclear Receptor Related; NGFI-B/Nur77 Beta-Type Transcription Factor Homolog; Nuclear Receptor Subfamily 4, Group A, Member 2; Nur Related Protein-1, Human Homolog Of 3 Intermediate-Early Receptor Protein; Orphan Nuclear Receptor NR4A2; T-Cell Nuclear Receptor NOT; Nuclear Receptor Related 1; IDLDP

NURR1 (NR4A2) is a transcription factor that regulates the dopamine signaling pathway and critically influences the differentiation, maturation and maintenance of dopaminergic neurons in the midbrain. NURR1 is found in various regions of the central nervous system, including the cortex, hippocampus, brainstem, spinal cord and olfactory bulb¹³⁴
Mice in which NURR1 was deactivated (NURR1-KO mice) developed hyperactivity and impulsivity, but not the other ADHD symptoms such as anxiety, physical coordination problems, altered social behavior or memory problems. Neither tyrosine hydroxylase (which limits catecholamine synthesis) nor dopamine levels were altered by NURR1 blockade. Hyperactivity caused by NURR1 deactivation was reversed by methylphenidate.¹³⁵ Nurr1-KO mice (Nurr1-/-) are unable to develop dopaminergic neurons in the midbrain and die shortly after birth. These mice show impaired motor function and a significant loss of dopaminergic neurons in the SNpc and the VTA. The expression of NURR1 in midbrain dopaminergic neurons decreases with age, which coincides with the increased morbidity of Parkinson’s disease¹³⁴
NURR1 regulates - in interaction with other factors - the expression of TH, AADC and VMAT2, which are essential for the synthesis, storage and release of dopamine. In addition, NURR1 activates the transcription of the TH gene, whereby NURR1 exerts considerable influence on dopamine synthesis.
NURR1 mutations and polymorphisms causing either reduced expression or dysfunction have been associated with familial and sporadic Parkinson’s disease¹³⁴

The NR4A2 (NURR1) protein is a member of the steroid thyroid hormone retinoid receptor superfamily. NR4A2 is a transcriptional regulator important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is critical for the expression of a number of genes such as SLC6A3, SLC18A2, TH and DRD2, which are essential for the development of mdDA neurons. Mutations in this gene have been linked to diseases associated with dopaminergic dysfunction, including Parkinson’s disease, schizophrenia and manic depression. Dysregulation of this gene may be associated with rheumatoid arthritis. ¹³⁶
NR4A2 is associated with

• Intellectual development disorder with speech impairment
• early-onset dopa-reactive dystonia-parkinsonism
• Parkinson’s disease, late onset

Paralog: NR4A3

1.122. CSMD1, CUB And Sushi Multiple Domains 1¶

Other names: KIAA1890, PPP1R24, Protein Phosphatase 1, Regulatory Subunit 24, CUB And Sushi Domain-Containing Protein 1, CUB And Sushi Multiple Domains Protein 1

The protein CSMD1 is probably involved in learning and memory, branching of the mammary glands during pregnancy and development of the reproductive organs. CSMD1 is probably an integral component of the membrane. CSMD1 is a potential suppressor of squamous cell carcinoma.¹³⁷

CSMD1 is associated with

• Autism
• Schizophrenia¹³⁸
• Anorexia nervosa¹³⁹

CSMD1 belongs to the same signaling pathway as CREB3, PTPRD and GAB1, and is involved in neuron differentiation and the **dopamine pathway **.¹³⁹
CSMD1 plays a role in the ratio between dopamine and serotonin metabolites In the cerebrospinal fluid.¹⁴⁰
CSMD1:c.3335A > G (p.E1112G) and c.4071C > G (p.I1357M) were identified as candidate genes for Parkinson’s disease, which is also caused by dopamine disorders.¹⁴¹

One study found CSMD1 to be one of the 51 most likely gene candidates for ADHD.⁷ One study found CSMD1 (variant rs6559123) to be one of the 20 most likely among 96 ADHD candidate genes.¹⁴²

Potassium channels influence dopamine¶

The function of potassium channels can influence dopaminergic tone. Therefore, potassium channels may be involved in the development of ADHD, but also schizophrenia and ASD.^143144145146

1.85. KCNJ6, Potassium Inwardly Rectifying Channel Subfamily J Member 6¶

Other names: GIRK2; KATP2; BIR1; G Protein-Activated Inward Rectifier Potassium Channel 2; HiGIRK2; KCNJ7; Inward Rectifier K(+) Channel Kir3.2; Kir3.2; GIRK-2; KATP-2; Potassium Inwardly-Rectifying Channel, Subfamily J, Member 6; Potassium Channel, Inwardly Rectifying Subfamily J, Member 6; Potassium Channel, Inwardly Rectifying Subfamily J Member 6; Potassium Voltage-Gated Channel Subfamily J Member 6; Inward Rectifier Potassium Channel KIR3.2; KIR3.2; KPLBS

KCNJ6 is a member of the family of G protein-coupled inwardly rectifying potassium channels. This type of potassium channel allows a greater flow of potassium into the cell than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as the external potassium is increased, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blocking of the outward current by internal magnesium. These proteins modulate many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells, through the stimulation of G protein-coupled receptors. The potassium channel KCNJ6 may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors.

GeneCards summary for the KCNJ6 gene
KCNJ6 (Potassium Inwardly Rectifying Channel Subfamily J Member 6) is a protein-coding gene. The diseases associated with
KCNJ6 is associated with

• Keppen-Lubinsky syndrome (generalized lipodystrophy-progeroid features-severe intellectual disability syndrome)
  • rare disease (less than 1 / 1,000,000)
  • severe developmental delay
  • Facial dysmorphism
  • mental disability
• Epilepsy
• ADHD

Related signal paths:

• Potassium channels
• Progeria-associated lipodystrophy
• Activity of the inward potassium channel
• Activity of the G protein-activated inwardly rectifying potassium channel

Paralog: KCNJ5

OMIM: KCNJ6, POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 6

KCNJ6 regulates the excitability of dopaminergic neurons and is expressed in brain regions involved in ADHD.
KCNJ6 rs7275707 is associated with ADHD in children and correlates with increased reward dependence.
Both KCNJ6 rs7275707 and KCNJ6 rs6517442 affected EEG in the N-back task in ADHD.
KCNJ6 rs6517442 influenced the activation of the ventral striatum during reward anticipation.¹⁴³

1.67. DPP10, dipeptidyl peptidase like 10 (chromosome 2q14.1)¶

Other names: DPRP3; DPL2; DPPY; Dipeptidyl Peptidase IV-Related Protein 3; Dipeptidyl Peptidase-Like Protein; Dipeptidyl Peptidase 10 (Inactive); Inactive Dipeptidyl Peptidase 10; Dipeptidyl Peptidase X; DPRP-3; DPP X; Dipeptidyl Peptidase 10 (Non-Functional); Dipeptidyl Peptidase 10; Dipeptidyl Peptidase 10; Dipeptidyl Peptidase 10; KIAA1492

The DPP10 protein is a single-pass type II membrane protein from the S9B family in the clan SC of serine proteases. It appears to have no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it binds specific voltage-dependent potassium channels and alters their expression and biophysical properties.
DPP10 mutations are associated with

• Asthma
• Autism Spectrum Disorders

OMIM: DIPEPTIDYL PEPTIDASE X; DPP10

DPP10 correlates with ADHD.¹⁵, SNP: rs272000 116372265; Within 50 kb downstream of DPP10 with p: 9.10E-06¹⁴⁷ One study found a correlation with ADHD for the variant cg19651219, but not for the variants cg22670147, cg19651219, cg24654266, cg21322022, cg00089091 or cg19211931¹⁴⁴

1.268. KCNC2, Potassium Voltage-Gated Channel Subfamily C Member 2¶

Other names: Potassium Channel, Voltage Gated Shaw Related Subfamily C, Member 2; Potassium Voltage-Gated Channel, Shaw-Related Subfamily, Member 2; Voltage-Gated Potassium Channel Kv3.2; Shaw-Like Potassium Channel; Kv3.2; DEE103; KV3.2

The protein KCNC2 belongs to the class of delayed rectifying channel proteins and is an integral membrane protein that mediates the voltage-dependent permeability of potassium ions in excitable membranes. Due to sequence similarity, this gene is similar to the Shaw subfamily of the Shaker gene family of Drosophila.
KCNC2 is associated with

• Developmental and epileptic encephalopathy 103
• extratemporal epilepsy

Related signaling pathways:

• Integration of the energy metabolism
• Potassium channels / ion channel activity
• delayed rectifier potassium channel activity

Paralog: KCNC4

KCNC2 contributes to the regulation of rapid repolarization of the action potential and to sustained high-frequency firing in neurons of the central nervous system. Homotetramer channels mediate delayed-rectifying voltage-dependent potassium currents that are rapidly activated and slowly inactivated at high-threshold voltages. They form tetrameric channels through which potassium ions migrate depending on their electrochemical gradient. The channel switches between open and closed conformation in response to the voltage difference across the membrane. Can form functional homotetrameric and heterotetrameric channels containing variable proportions of KCNC1 and possibly other family members; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties can be modulated either by association with additional subunits such as KCNE1, KCNE2 or KCNE3 or indirectly by nitric oxide (NO) via a cGMP- and PKG-mediated signaling cascade that slows channel activation and deactivation of delayed rectification potassium channels (By similarity). Contributes to the firing of sustained trains of very short action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic neurons (SCN), and hippocampal and neocortical interneurons. The frequency of the sustained maximal action potential in hippocampal inhibitory interneurons is negatively modulated by activation of the histamine H2 receptor in response to phosphorylation by cAMP and protein kinases (PKA). Plays a role in maintaining the reliability of synaptic transmission in neocortical GABA-ergic interneurons by generating action potential (AP) repolarization at nerve terminals, thereby reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for synchronization of long-distance gamma oscillations in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potentials in neurons of the suprachiasmatic nucleus (SCN) in a light-dependent manner¹⁴⁸

One study found KCNC2 (variant rs17114649) to be one of 96 ADHD candidate genes.¹⁴²

1.100. DPP6, dipeptidyl-aminopeptidase-like protein 6¶

Other names: Dipeptidyl Peptidase Like 6, DPPX, DPL1, Dipeptidyl Aminopeptidase-Like Protein 6, Dipeptidyl Peptidase VI, Dipeptidyl-Peptidase 6, Dipeptidyl Peptidase 6, DPP VI

DPP6 is a single-pass type II membrane protein of the S9B family in the clan SC of serine proteases. DPP6 has no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it binds specific voltage-dependent potassium channels and alters their expression and biophysical properties.¹⁴⁹
DPP6

• promotes the cell surface expression of the potassium channel KCND2
• modulates the activity and gating properties of the potassium channel KCND2
• has no dipeptidylaminopeptidase activity

Diseases associated with DPP6 are:

• Intellectual development disorder, autosomal dominant 33
• Ventricular fibrillation, Paroxysmal Familial, 2.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.64. KCNC1 (chromosome 11p15.1)¶

Other names: POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 1

The KCNC1 protein is a member of a family of integral membrane proteins that mediate the voltage-dependent permeability of potassium ions in excitable membranes. KCNC1 influences the dopamine-DARPP32 feedback on the cAMP pathway.¹⁵⁰
Alternative splicing appears to lead to two isoforms with different C-termini.
Diseases associated with KCNC1 are epilepsy, progressive myoclonic 7 and spinocerebellar ataxia 13.

OMIM: POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 1

• SNP: rs3893215 Position: 7721406; In intron of KCNC1¹⁴⁷
  p: 2.56E-05

1.65. KCNIP4, Potassium Voltage-Gated Channel Interacting Protein 4 (chromosome 4p15.3-p15.2)¶

Other names: KCHIP4; CALP; A-Type Potassium Channel Modulatory Protein 4; Kv Channel Interacting Protein 4; Kv Channel-Interacting Protein 4; Calsenilin-Like Protein; MGC44947; Potassium Channel-Interacting Protein 4; KChIP4

The protein KCNIP4 is a member of the family of voltage-dependent potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the recoverin branch of the EF-hand superfamily. The members of the KCNIP family are small calcium-binding proteins with EF-hand-like domains that differ from each other by the N-terminus. They are integral subunit components of native Kv4 channel complexes. They can regulate A-type currents and thus neuronal excitability in response to changes in intracellular calcium. KCNIP4 also interacts with presenilin. KCNIP4 is involved in cardiac excitatory conduction, in the regulation of nuclear beta-catenin signaling and in the transcription of target genes.¹⁵¹
KCNIP4 is associated with

• Synovial angioma
• congenital capillary malformations

OMIM: POTASSIUM CHANNEL-INTERACTING PROTEIN 4, KCNIP4

• SNP rs876477 Position: 20766026; Intron of KCNIP4¹⁴⁷
  p: 2.69E-05

1.66. KCNIP1, Potassium Voltage-Gated Channel Interacting Protein 1¶

Other names: KCHIP1; A-Type Potassium Channel Modulatory Protein 1; Kv Channel Interacting Protein 1; Kv Channel-Interacting Protein 1; Vesicle APC-Binding Protein; VABP; Potassium Channel Interacting Protein 1; Potassium Channel-Interacting Protein 1; KChIP1

KCNIP1 is a member of the cytosolic voltage-gated potassium (Kv) channel-interacting protein (KCNIPs) family of neuronal calcium sensors (NCS) of calcium-binding EF-hand proteins. They associate with Kv4 alpha subunits to form native Kv4 channel complexes. KCNIP1 can regulate fast inactivating (A-type) currents and thus neuronal membrane excitability in response to changes in intracellular calcium concentration. KCNIP1 regulates channel density, inactivation kinetics and the rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. KCNIP1 modulates KCND1/Kv4.1 and KCND2/Kv4.2 currents in vitro. KCNIP1 increases the presence of KCND2 at the cell surface.¹⁵²
KCNIP1 is associated with

• Epilepsy, idiopathic generalized
• Hypertension, diastolic

Related signal paths:

• cardiac conduction
• Calcium ion binding
• Protein N-terminus binding

Paralog: KCNIP4

OMIM: POTASSIUM CHANNEL-INTERACTING PROTEIN 1; KCNIP1

The SNP rs1541665 Position: 170075495; Intron of KCNIP1 correlates with ADHD.¹⁴⁷¹⁵³

1.256. ALG10, ALG10 alpha-1,2-glucosyltransferase¶

Other names: ALG10A; DIE2; Dolichyl-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-dolichol alpha-1,2-glucosyltransferase; Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase; Asparagine-Linked Glycosylation Protein 10 Homolog A; Alpha-1,2-glucosyltransferase ALG10-A; Alpha-2-glucosyltransferase ALG10-A; FLJ14751; Asparagine-Linked Glycosylation 10, Alpha-1,2-glucosyltransferase Homolog (S. Pombe); Asparagine-Linked Glycosylation 10, Alpha-1,2-Glucosyltransferase Homolog (Yeast); Asparagine-Linked Glycosylation 10 Homolog (Yeast, Alpha-1,2-Glucosyltransferase); Asparagine-Linked Glycosylation 10, Alpha-1,2-Glucosyltransferase Homolog; Derepression Of ITR1 Expression 2 Homolog (S. Cerevisiae); Derepression Of ITR1 Expression 2 Homolog; Potassium Channel Regulator 1; Alpha2-Glucosyltransferase; EC 2.4.1.256; EC 2.4.1.16; EC 2.4.1; KCR1

ALG10 is a membrane-associated protein that attaches the third glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. ALG10 transfers the terminal glucose from dolichylphosphate glucose (Dol-P-Glc) to the lipid-linked oligosaccharide Glc2Man9GlcNAc(2)-PP-Dol. The rat protein homolog has been shown to specifically modulate the gating function of the rat neuronal ether-a-go-go (EAG) potassium ion channel.¹⁵⁴
ALG10 is associated with

• Long-Qt syndrome 2
• Toxic myocarditis

Related signaling pathways:

• Transport to the Golgi and subsequent modification
• Initial phase of N-glycosylation of proteins (eukaryotic)

Paralog: ALG10B

One study found ALG10 rs1843014) to be one of 96 ADHD candidate genes.¹⁴²

Other dopaminergic influences¶

1.30. ADGRL3, LPHN3, latrophilin-3 (chromosome 4q13.1)¶

Other names: ADHESION G PROTEIN-COUPLED RECEPTOR L3; Adhesion G Protein-Coupled Receptor L3; LEC3; KIAA0768; LPHN3; Calcium-Independent Alpha-Latrotoxin Receptor 3; Latrophilin-3; Latrophilin Homolog 3 (Cow); Latrophilin 3; Lectomedin 3; Lectomedin-3; CIRL-3; CIRL3; CL3

ADGRL3 is a G protein-coupled receptor of the adhesion receptor subfamily. ADGRL3 regulates synaptic function and serves maintenance in brain regions that mediate locomotor activity, attention, and place and route memory.
Latrophilins can play a role in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS domain (G protein-coupled receptor proteolysis site) resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with considerable similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound to the cell membrane. ADGRL3 plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3 expressed at the surface of neighboring cells. ADGRL3 plays a role in the development of glutamatergic synapses in the cortex. ADGRL3 is important in determining connectivity rates between principal neurons in the cortex.¹⁵⁵
ADGRL3 is associated with

• Sialuria
• Amed syndrome, Digenic

Related signaling pathways:

• GPCRs, class B secretin-like
• GPCRs, other
• G-protein-coupled receptor activity
• Carbohydrate binding

Paralog: ADGRL2

OMIM: Latrophilin-3 (LPHN3) gene / ADHESION G PROTEIN-COUPLED RECEPTOR L3; ADGRL3 gene

ADGRL3(LPHN3)-KO mice represent an animal model for ADHD.¹⁵⁶ ADGRL3-KO mice show:¹⁵⁷

• Hyperactivity in a new environment and on cocaine
  - increased dopamine and serotonin levels in the striatum
• altered dopamine and serotonin receptor expression
  - altered expression of DAT, Calcium signaling and other cell adhesion proteins.
  ADGRL3 is involved in the regulation of the amount, duration and frequency of DA release in the neostriatum (caudate-putamen).¹⁵⁷

ADGRL3 is a candidate gene for ADHD.^1158159160
ADGRL3 binds to Gαi1, Gαi2, Gαs, Gαq and Gα13. In particular, gene variants that cause impaired Gα13 binding appear to be relevant in ADHD.¹⁶¹ SNPs in ADGRL3 showed a correlation with ADHD symptom severity and a potential pleiotropic effect on different domains of ADHD severity.¹⁶² ADGRL3 gene variants interact with gene variants on chromosome 11q (in a region spanning the NCAM1, TTC12, ANKK1, and DRD2 genes) and dramatically increase ADHD risk and severity in young children.^163164165158 A combination of ADGRL3 rs65511665 and a haplotype in 11q increases the risk of ADHD by 2.5-fold.¹⁶⁶
ADGRL3 rs2345039 is a predictor of ADHD-C with persistence of symptoms into adolescence¹⁶³
ADGRL3 rs65511665 correlates with increased ADHD prevalence and a highly comorbid disruptive behavior subtype.¹⁶⁵¹⁶⁷ ADGRL3 rs65511665 correlates with response to stinulants ¹⁶⁵¹⁶⁷

1.296. SORCS3, Sortilin Related VPS10 Domain Containing Receptor 3¶

Other names: KIAA1059; SORCS; VPS10 Domain-Containing Receptor SorCS3; Sortilin-Related VPS10 Domain Containing Receptor 3; VPS10 Domain Receptor Protein SORCS 3 (SORCS3)

SORCS3 is a type I receptor transmembrane protein of the vacuolar protein sorting 10 family of receptors. The proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for processing by proprotein convertase, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is highly expressed in the brain.¹⁶⁸
SorCS is expressed in a unique transient and dynamic pattern in regions where cells are proliferating and in areas where differentiated cells are already present, including the cortex, VTA and globus pallidus. SorCS expression begins with the onset of differentiation of dopaminergic neurons and declines to low levels in adulthood. The VTA projects dopaminergically to the basal ganglia, the amygdala and the cerebral and piriform cortex. These areas are also characterized by the presence of dopaminergic neurons and express SorCS. This suggests a possible function of SorCS in the development of dopaminergic pathways.¹⁶⁹
SORCS3 is associated with

• ADHD
• Alzheimer’s disease
  • silencing of the SORCS3 gene in cell cultures led to increased processing of the amyloid precursor protein

Related signal paths:

• Neuropeptide receptor activity

Paralog: SORCS1

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁷⁰¹⁷¹

1.76. DIRAS2; DIRAS FAMILY, GTP-BINDING RAS-LIKE PROTEIN 2 (chromosome 9q22.2)¶

The protein DIRAS2 (Di-Ras2) belongs to a branch of the functionally diverse Ras superfamily of monomeric GTPases. Ras play a role in cell morphogenesis and neurogenesis.
The effector mechanisms of DIRAS2 are largely unknown. In contrast to other Ras kinases, DIRAS2 does not activate MAP kinase, phosphoinositide 3-kinase or the AKT signaling pathway. DIRAS2 shows low GTPase activity and is predominantly present in the GTP-bound form. It is even unclear whether DIRAS2 is regulated by GTP binding at all.¹⁷² DIRAS2 is particularly highly expressed in lower raphe serotonin neurons¹⁷³, which could indicate a contribution to the regulation of the caudal serotonergic system.
DIRAS2 inhibited colorectal cancer cell proliferation and affected the expression of cell cycle proteins. DIRAS2 blocked the signaling pathways of NF-kB, leading to G0/G1 arrest. DIRAS2 interacted with the regulatory subunit 2 of the 26S proteasome (PSMD2), which is not an ATPase, facilitating proteasome-mediated degradation of DIRAS2. DIRAS2 is degraded by PSMD2 in a proteasome-mediated manner. DIRAS2 inhibited nuclear expression of P65 in both RKO and HT29 cells.¹⁷⁴ DIRAS2 reduced the ability of SmgGDS (a chaperone protein and guanine nucleotide exchange factor, RAP1GDS1) to interact with the RNA polymerase I transcription factor upstream binding factor (UBF) and to localize to the nucleolus and act as a tumor suppressor.¹⁷⁵

In the human brain, DIRAS2 is mainly expressed in the hippocampus, PFC, ACC and amygdala.¹⁷²¹⁷⁶ During brain development, Diras2 increases strongly in mice from the prenatal to the late postnatal stage. Diras2 is expressed in glutamatergic and catecholaminergic neurons.¹⁷⁶

DIRAS2 acts as a tumor suppressor gene in cutaneous melanoma by inhibiting Wnt/β-catenin signaling. It is also associated with immune infiltration in cutaneous melanoma,¹⁷⁷ with papillary thyroid microcarcinoma¹⁷⁸ and colorectal carcinoma (the most common gastrointestinal cancer) .¹⁷⁴

OMIM: DIRAS FAMILY, GTP-BINDING RAS-LIKE PROTEIN 2; DIRAS2

DIRAS2 blocks the action of Nf-kB.¹⁷⁴
This may represent a pathway to dopamine, as Nf-kB regulates striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) expression in the striatum. NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:¹⁷⁹

• more A2AAR
• less A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperone bond
• increased G(alphaolf) and G(alphas) proteins
  • these transmit A2AAR signals
    -reduced G(alphai1) protein
    this forwards signals from A1AR and D2R

Nf-kB p50-KO mice showed increased locomotor activity in response to caffeine.

DIRAS2 is a candidate gene for ADHD.¹⁷⁶ Indications of a correlation with ADHD were found in:¹⁷²

• A allele of rs1331503
• T allele of rs1412005
• Haplotype ACGCTT from block 2 (consisting of the SNPs rs1331503, rs2297354, rs1331504, rs7848810, rs1412005 and rs689687

DIRAS2 is not only associated with ADHD, but also with bipolar disorder and Parkinson’s disease. A cross-disorder analysis for all disorders together (ADHD, bipolar and Parkinson’s) showed a 13% risk increase for the rs1412005 T allele.¹⁷²
The association with ADHD and Parkinson’s could indicate that DIRAS2 influences the dopaminergic system.

1.90. TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1¶

The protein TLE1 is part of the beta-catenin-TCF complex. It is found in the cytosol and nucleoplasm.
TLE1:¹⁸⁰

• enables identical protein binding activity and transcriptional corepressor activity.
• binds to a number of transcription factors
• Inhibition of transcriptional activation mediated by FOXA2 and by members of the CTNNB1 and TCF families in Wnt signaling
• Enhancement of FOXG1/BF-1 and HES1-mediated transcriptional repression
• Inhibition of signaling and expression of NF-kappa-B / kappa-B kinase
• Inhibition of the anoikis
• influences development-Notch signaling pathway
• influences RNA polymerase I promoter opening
• Coactivator for ESRRG

TLE1 is associated with the following diseases

• Nuclear binding factor Acute myeloid leukemia
• Glomerular tumor

TLE1 impaired NOD2 and thereby also Nf-kB signaling in the liver.¹⁸¹
This may represent a pathway to dopamine, as Nf-kB regulates striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) expression in the striatum. NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:¹⁷⁹

• more A2AAR
• less A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperone bond
• increased G(alphaolf) and G(alphas) proteins
  • these transmit A2AAR signals
    -reduced G(alphai1) protein
    this forwards signals from A1AR and D2R

Nf-kB p50-KO mice showed increased locomotor activity in response to caffeine.

OMIM: TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1

A study found a change in the expression of TLE1 in ADHD.¹⁰⁶ TLE1 had already been identified as a candidate gene for ADHD in another study.¹⁸²

1.125. FERMT3, FERM Domain Containing Kindlin 3¶

Other names: KIND3, MIG2B, URP2, UNC112C, UNC-112 Related Protein 2, Fermitin Family Homolog 3, Unc-112-Related Protein 2

The protein FERMT3 is a member of the Kindlin protein family, which mediates protein-protein interactions in integrin activation and thus plays a role in cell adhesion, migration, differentiation and proliferation. FERMT3 plays a key role in the regulation of hemostasis and thrombosis. FERMT3 contributes to the maintenance of the erythrocyte membrane skeleton and plays a central role in cell adhesion in hematopoietic cells. FERMT3 acts by activating integrin beta-1-3 (ITGB1, ITGB2 and ITGB3). FERMT3 is required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells as well as for the activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs). Isoform 2 can act as a repressor of NF-kappa-B and apoptosis.¹⁸³ Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages and upregulation of beta-2 integrins in all major arterial beds.¹⁸⁴
FERMT3 is associated with

• Leukocyte adhesion deficiency, type Iii
• Kindler syndrome

Inhibition of NF-kappa-B may represent a pathway to dopamine, as Nf-kB regulates striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) expression in the striatum. NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:¹⁷⁹

• more A2AAR
• less A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperone bond
• increased G(alphaolf) and G(alphas) proteins
  • these transmit A2AAR signals
    -reduced G(alphai1) protein
    this forwards signals from A1AR and D2R

Nf-kB p50-KO mice showed increased locomotor activity in response to caffeine.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.82. GLI1; PPD1; GLI Family Zinc Finger 1¶

Other names: GLI; Glioma-Associated Oncogene Homolog 1 (Zinc Finger Protein); Zinc Finger Protein GLI1; Oncogene GLI; Glioma-Associated Oncogene Family Zinc Finger 1; GLI-Kruppel Family Member GLI1; Glioma-Associated Oncogene 1; Glioma-Associated Oncogene; PAPA8; PPD1

The protein GLI1 is a member of the Kruppel family of zinc finger proteins. GLI1 acts as a transcription factor, is activated by the Sonic Hedgehog signal transduction cascade and regulates stem cell proliferation. GLI1 is an effector molecule of the Hedgehog (Hh) signaling pathway. The activity and nuclear localization of GLI1 is negatively regulated by p53 in an inhibitory loop.¹⁸⁵
GLI1 is associated with

• Polydactyly, postaxial, type A8
• Polydactyly, preaxial I

Related signal paths:

• dopaminergic neurogenesis
• GPER1 signal transmission
• Chromatin binding
• Microtubule binding

The timing of Gli1 and Sonic Hedgehog expression separates midbrain dopamine neurons.¹⁸⁶ Gli1 protects nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration in Parkinson’s disease models.¹⁸⁷

Paralog: GLI2

GLI1 binds to the DNA consensus sequence 5’-GACCACCCA-3’.GLI1 regulates the transcription of specific genes during normal development. GLI1 plays a role in craniofacial development and digital development as well as in the development of the central nervous system and the gastrointestinal tract. GLI1 mediates SHH signaling. GLI1 plays a role in cell proliferation and differentiation via its role in SHH signaling.
[Isoform 2]: Acts as a transcriptional activator, but activates a different set of genes than isoform 1. Isoform 2 activates the expression of CD24, unlike isoform 1. Isoform 2 mediates SHH signaling and promotes cancer cell migration.

One study found increased expression and decreased methylation of GLI2 in ADHD.¹²⁶

1.307. DGKH; Diacylglycerol Kinase Eta¶

Other names: DGKeta; diglyceride kinase Eta; DAG kinase Eta; EC 2.7.1.107; DGK-Eta; diacylglycerol kinase η

The DGKH protein is a member of the diacylglycerol kinase (DGK) enzyme family. Diacylglycerol kinases (DGKs) are a group of ten enzymes that metabolize 1,2,diacylglycerol (DAG) to phosphatidic acid (PA). They all contain a conserved C’-terminal catalytic domain and two cysteine-rich Zn2+ finger motifs with different regulatory domains. Diacylglycerol kinases (DGKs) are involved in the regulation of intracellular concentrations of diacylglycerol and phosphatidic acid. DGKH probably acts as a central switch between the signaling pathways activated by diacylglycerol and phosphatidic acid with different cellular targets and opposing effects in numerous biological processes. DGKH plays a key role in promoting cell growth. DGKH activates the Ras/B-Raf/C-Raf/MEK/ERK signaling pathway induced by EGF. DGKH regulates the recruitment of RAF1 and BRAF from the cytoplasm into the membranes and their heterodimerization.¹⁸⁸
DGKH is associated with

• Bipolar Disorder
• Nephrolithiasis

Related signal paths:

• downstream GPCR signaling
• Response to elevated platelet cytosolic Ca2+
• NAD+ kinase activity
• Diacylglycerol kinase activity

DGKH expression increases during mouse brain development, suggesting a possible role for this kinase in late developmental stages. Immunostaining revealed strong DGKH expression in the hippocampus and cerebellum in mice and in the striatum in humans .

Dopamine and the phosphorylated dopamine transporter are increased in DGKH-KO mice.¹⁸⁹

Hains and Arnsten describe an influence of DGKH on stress regulation. Excessive dopaminergic D1 receptor stimulation impairs prefrontal function via intracellular cAMP signaling, leading to disruption of prefrontal networks, while excessive noradrenergic stimulation of alpha1 receptors impairs prefrontal function via intracellular phosphatidylinositol protein kinase C signaling. DISC1, RGS4 and DGKH normally serve to inhibit intracellular phosphatidylinositol protein kinase C signaling and thus serve as brakes on intracellular signaling pathways. Mutations that result in the loss of adequate function of these genes are likely to weaken endogenous regulation of these signaling pathways, explaining the susceptibility to stress and the severe loss of PFC regulation of behavior, thought and affect (including thought disorder, disinhibition and impaired working memory) in the disorders associated with these gene mutations.¹⁹⁰

Paralog: DGKD

A DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with adult ADHD, bipolar disorder (rs1170169 and rs9525580) and depression, while the complementary AGC haplotype was protective.¹⁹¹ One study found no evidence of environmental gene interactions in relation to rs994856/rs9525580/rs9525584 GAT in ADHD.¹⁹²

1.101. EMP2, Epithelial Membrane Protein 2¶

Other names: XMP, Protein XMP, EMP-2

EMP2 is a tetraspan protein of the PMP22/EMP family. EMP2 regulates the composition of the cell membrane. It influences¹⁹³

• Endocytosis
• Cell signaling
• Cell proliferation
• Cell migration
• Cell adhesion
• Cell death
• Cholesterol homeostasis
• Albumin excretion in urine
• Embryo implantation
• promotes angiogenesis and vasculogenesis through induction of VEGFA via a HIF1A-dependent pathway
• inhibits caveolin-1 by increasing lysosomal degradation
• activates PTK2 and thereby regulates the density of focal adhesion, F-actin conformation and cell adhesion capacity
• modulates the function of certain integrin isomers in the plasma membrane
• regulates the surface expression of MHC1 and ICAM1
• EMP2 deficiency (e.g. in EMP2-KO mice) alters placental angiogenesis and mimics features of human placental insufficiency.¹⁹⁴ This can trigger oxygen deficiency. Hypoxia, in turn, is known to cause a change in the dopamine system. For example, oxygen deprivation during birth is a possible cause of ADHD.

EMP2 is associated with the following diseases

• nephrotic syndrome
• genetic steroid-resistant nephrotic syndrome

Related paths:

• Protein kinase binding
• Kinase binding

Paralog: PMP22

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.317. SYN3, Synapsin III¶

Other names: Synapsin-3, CN28H9.2 (Synapsin III)

The SYN3 protein corresponds to the domain model of the synapsin family, with domains A, C and E having the highest degree of conservation. The protein contains a unique domain J, which is located between domains C and E. Due to the localization of this gene to 22q12.3, a possible schizophrenia susceptibility locus, and the established neurobiological role of synapsins, this family member may represent a candidate gene for schizophrenia. The TIMP3 gene is located in an intron of this gene and is transcribed in the reverse direction.¹⁹⁵

SYN3 is associated with

• Sorsby fundus dystrophy
• Fundus dystrophy

Related signal paths:

• Neurotransmitter release cycle
• Transmission via chemical synapses
• Synaptogenesis

Paralog: SYN2

Syn III controls the earliest stages of dopaminergic neuron development in vertebrates and mammals.Polymorphisms in the synapsin III (Syn III) gene are associated with ADHD and affect MPH responding. MPH can bind SYN3. The observed SYN3 polymorphism appears to influence the onset of ADHD and response to MPH by impairing BDNF-dependent development of dopaminergic neurons.¹⁹⁶

1.318. SYN1, Synapsin 1¶

Other names: Synapsin I, Synapsin-1, Brain Protein 4.1; MRX50; Mental Retardation, X-Linked 50; Synapsin Ib; EPILX; SYN1a; SYN1b; SYNI

Synapsins encode neuronal phosphoproteins that bind to the cytoplasmic surface of synaptic vesicles. Synapsins are characterized by common protein domains and are involved in synaptogenesis and the modulation of neurotransmitter release.
Synapsin-I (SYN1) is a presynaptic phosphoprotein that is crucial for synaptogenesis and synaptic plasticity. SYN1 plays a role in the regulation of axonogenesis and synaptogenesis. The encoded protein serves as a substrate for several different protein kinases, and phosphorylation may play a role in the regulation of this protein in the nerve terminal¹⁹⁷

SYN1 is associated with:

• X-linked disorders with primary neuronal degeneration, which mainly affect men.
  • Rett syndrome

A study of 31 individuals found 22 different SYN1 variants¹⁹⁸

Syn1 abnormalities correlate with:¹⁹⁸

• ASD or ADHD in 91% of people with ADHD
• Epilepsy at 82 %
  • mainly tonic-clonic or focal seizures with impaired consciousness
  • Reflex seizures are one of the most representative clinical manifestations associated with SYN1
  • Trigger:
    • Contact with water (> 50 %)
    • Rubbing with a towel
    • Fever
    • Brushing your teeth
    • Fingernail clipping
    • Fall asleep
    • Watching other people showering or bathing
    • Hyperpnea
    • Emotions
    • Light
    • Stroboscope
    • Digestive problems
    • Bowel movement
• mental disability at 77 %
  • correlates with early age of onset of seizure
• Developmental delay at 70%

The molecular spectrum of SYN1 variants is broadly diversified

• aborting variants (frameshift, nonsense, splice and start-loss variants)
  • Epilepsy more common
• non-terminating variants (missense substitutions and in-frame duplications)

Noradrenaline¶

Noradrenaline synthesis¶

1.7. DBH, dopamine beta-hydroxylase (chromosome 9q34.2; Taql A)¶

The enzyme dopamine β-hydroxylase catalyzes the oxidation of dopamine to noradrenaline.

DBH is a candidate gene for ADHD ^{12 1471}
The C allele of the rs129882 SNP associated with ADHD halved luciferase activity. Reduced DBH expression would be associated with reduced conversion of dopamine to noradrenaline and thus a relative hypo-noradrenergic state in ADHD.¹⁹⁹

DBH also appears to be a candidate gene for ASD²⁰⁰

Noradrenaline effect¶

1.46. ADRA1A, ALPHA-1A-ADRENERGIC RECEPTOR (chromosome 8p21.2)¶

OMIM: ALPHA-1A-ADRENERGIC RECEPTOR; ADRA1A

The HES1 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.017.³

1.17. ADRA2A, ALPHA-2A-ADRENERGIC RECEPTOR (chromosome 10q25.2)¶

OMIM: ALPHA-2A-ADRENERGIC RECEPTOR; ADRA2A

ADRA2A is a candidate gene for ADHD.¹¹⁴⁷⁸⁵

None of the ADRA2A polymorphisms MspI and DraI correlated significantly with the response to MPH as a whole. However, carriers of the G allele of the MspI polymorphism showed a correlation with a significant improvement in inattention symptoms.²⁰¹
The alpha-2A-adrenergic receptor gene polymorphism modulates gray matter structural networks, visual memory and inhibitory cognitive control in children with attention-deficit/hyperactivity disorder²⁰²

1.69. ADRA2C, ALPHA-2C-ADRENERGIC RECEPTOR (chromosome 4p16.3)¶

OMIM: ALPHA-2C-ADRENERGIC RECEPTOR

Source¹⁴⁷

1.44. ADRB2, BETA-2-ADRENERGIC RECEPTOR (chromosome 5q32)¶

OMIM: BETA-2-ADRENERGIC RECEPTOR; ADRB2

The ADRB2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.013.³

Noradrenaline reduction¶

Noradrenaline reuptake¶

1.18. NET, noradrenaline transporter gene (chromosome 16q12.2)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, NORADRENALINE), MEMBER 2; SLC6A2

The noradenaline transporter reuptakes more dopamine than noradrenaline in the PFC. See therefore above under dopamine reuptake.

Of the four polymorphisms of the NET gene

• rs5569
• rs28386840
• rs2242446
• rs3785143
  showed carriers of the T allele of the polymorphism rs28386840
• significantly more frequent response to MPH
• significantly greater improvement in hyperactive-impulsive symptoms
  than the carriers of the other polymorphisms.
  ²⁰¹

Development of the noradrenaline system¶

1.329. MECP2¶

In the MeCP2 mutant mouse model of Rett syndrome, the HPA axis is overactivated, presumably due to increased expression of the CRH gene, leading to abnormal stress responses. MeCP2 binds the CRH promoter, which is normally enriched with methylated CpG dinucleotides.²⁰³ MeCP2 deficiency impairs the noradrenergic system and causes respiratory distress. The administration of noradrenaline improves this.²⁰⁴

Reduced MECP2 expression was found in 11 of 14 people with ASD and in 2 of 2 people with ADHD.²⁰⁵ One case study also reported an association with ADHD.²⁰⁶ SHR and PCB-contaminated rats showed changes in the MECP2 gene.²⁰⁷ The offspring of rat mothers who had been given alcohol showed reduced MECP2 expression.²⁰⁸²⁰⁹ Alcohol during pregnancy massively increases the risk of ADHD.

Serotonin¶

Serotonin synthesis¶

1.16. Tryptophan hydroxylase gene (chromosome 11p15.1)¶

Tryptophan hydroxylase is a candidate gene for ADHD.¹

1.77. TPH1, tryptophan hydroxylase 1 gene (chromosome 11p15.1)¶

OMIM: Tryptophan hydroxylase 1 gene; TPH1

One study found that the rare 218A-6526G haplotype of TPH1 was significantly more frequently not transmitted in subjects with ADHD.²¹⁰

Another study did not find any involvement of the more common haplotypes of TPH1 or TPH2 in ADHD-C.²¹¹

1.21. TPH2, tryptophan hydroxylase 2 gene (chromosome 12q21.1)¶

OMIM: Tryptophan hydroxylase 2 gene, TPH2

TPH2 is a candidate gene for ADHD.¹⁴⁷

The TPH2 gene was identified as a candidate gene for ADHD with p = 0.003 in a 2006 study.³ Another study was unable to confirm this for either TPH1 or TPH2.²¹¹

Stress-naive TPH2-/- mice (TPH2-KO mice) showed reduced dopamine levels in the hippocampus and PFC.²¹²
In TPH2+/- mice, stress led to reduced dopamine levels:²¹³

• In the hippocampus and striatum compared to stress-naïve TPH2+/- mice.
• In amygdala and PFC compared to stressed TPH2+/+ mice

The changes in the dopaminergic system of stressed TPH2+/- mice differed significantly from those in TPH2+/+ animals and were very similar to those in TPH2-/- mice.

Stressed TPH2-/- mice showed no particular changes in noradrenaline levels in the amygdala, PFC, hippocampus, dorsal raphe nuclei or striatum. They only showed (like TPH2+/+ mice) the usual increased noradrenaline levels in the PFC, hippocampus and striatum compared to non-stressed mice of the respective genotype.²¹³

The TPH2 variant rs17110747 showed behavioral and cognitive symptoms of ADHD only in females. There was a highly significant transmission of the G allele from the parents to the girls with ADHD. In addition, girls with the G/G genotype (rs17110747) responded better to placebo when assessed by their parents.²¹⁴

Serotonin effect¶

1.13. HTR1B, serotonin receptor 1B (chromosome 6q14.1)¶

Other names: 5-HYDROXYTRYPTAMINE RECEPTOR 1B

OMIM: 5-HYDROXYTRYPTAMINE RECEPTOR 1B

HTR-1B is a candidate gene for ADHD.¹⁴⁷¹

1.51. HTR1E, serotonin receptor 1E (chromosome 6q14.3)¶

Other names: 5-HYDROXYTRYPTAMINE RECEPTOR 1E

OMIM: 5-HYDROXYTRYPTAMINE RECEPTOR 1E; HTR1E

The HTRE1E gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.051.³

1.14. HTR2A, serotonin receptor 2A (chromosome 13q14.2)¶

Other names: 5-HYDROXYTRYPTAMINE RECEPTOR 2A

OMIM: 5-HYDROXYTRYPTAMINE RECEPTOR 2A

HTR-2A is a candidate gene for ADHD.¹⁴⁷¹

Serotonin degradation¶

Serotonin reuptake¶

1.15. SLC6A4, serotonin transporter gene, 5-HTT gene (chromosome 17q11.2)(x)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, SEROTONIN), MEMBER 4; 5-HTTLPR long

OMIM: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, SEROTONIN), MEMBER 4; SLC6A4;

SLC6A4 is a candidate gene for ADHD.¹⁴⁷¹¹²

Serotonin metabolization¶

1.20. Tryptophan 2,3-dioxynase (chromosome 4q32.1)¶

The enzyme tryptophan 2,3-dioxygenase (TDO) oxidizes L - tryptophan by binding to two oxygen atoms. This is the first and at the same time the rate-determining reaction step in the degradation of tryptophan.

The tryptophan 2,3-dioxynase gene is a candidate gene for ADHD.²¹⁵

Steroids¶

1.19. Androgen receptor (chromosome Xq11-q12)¶

The androgen receptor gene is a candidate gene for ADHD.²¹⁵

GABA¶

1.162. SLC6A12, GABA transporter¶

Other names: Solute Carrier Family 6 Member 12; BGT-1; Solute Carrier Family 6 (Neurotransmitter Transporter, Betaine/GABA), Member 12; Solute Carrier Family 6 (Neurotransmitter Transporter), Member 12; Sodium- And Chloride-Dependent Betaine Transporter; Na(+)/Cl(-) Betaine/GABA Transporter; Betaine/GABA Transporter-1; Gamma-Aminobutyric Acid Transporter; BGT1; GAT2

SLC6A12 encodes a GABA transporter.
The protein SLC6A12 is involved in monocarboxylic acid transport. SLC6A12 is probably localized in the plasma membrane and may be an integral part of the plasma membrane. SLC6A12 is probably active in neuronal projection. SLC6A12 transports betaine and GABA. It is likely to be relevant in the regulation of GABA-ergic transmission in the brain through the reuptake of GABA into presynaptic terminals as well as in osmotic regulation. Four 12-TM domain transporters have been identified that are localized in neurons and glia.²¹⁶
SLC6A12 is associated with

• Spinocerebellar ataxia 11
• Reflex epilepsy

SLC6A12 is a candidate gene for ADHD.²¹⁷

1.319. SLC6A1, GABA transporter¶

Other names: Solute Carrier Family 6 Member 1, GABATR, GAT1, Sodium- And Chloride-Dependent GABA Transporter 1; GABATHG; Solute Carrier Family 6 (Neurotransmitter Transporter, GABA), Member 1; Solute Carrier Family 6 (Neurotransmitter Transporter), Member 1; GABA Transporter 1; HGAT-1; GAT-1; GABT1; MAE

SLC6A1 encodes the GABA-1 transporter.

SLC6A1 is a candidate gene for ADHD.²¹⁸

1.22. GABA receptor alpha3 (chromosome Xq28)¶

OMIM: GABA receptor alpha3 gene

GABA receptor A3 is a candidate gene for ADHD.¹

OMIM indicates a function in relation to physical and psychological pain sensing as well as motor impairment and tolerance.

1.23. GABA receptor beta-3 (chromosome 15q11.2-q.12)¶

OMIM: GABA receptor beta 3 gene

GABA receptor B3 is a candidate gene for ADHD.¹

OMIM points out that GABA receptors are zinc-controlled and that a particularly zinc-insensitive polymorphism is known. OMIM does not mention any evidence of ADHD, but does mention autism, with which there is a high comorbidity in ADHD.
There are suggestions that ADHD and autism may have common neurological roots.²¹⁹
Zinc deficiency can cause ADHD (similar) symptoms.

1.35. CDH13, Cadherin13 (chromosome 16q23.3)¶

Other names: CDHH; T-Cadherin; H-Cadherin (Heart); Heart Cadherin; Cadherin-13; T-Cad; P105; Cadherin 13, H-Cadherin (Heart); runcated Cadherin; H-Cadherin

Cadherin-13 influences GABAergic function in the hippocampus and cognition.²²⁰
The prote9in CDH13 is a member of the cadherin superfamily. CDH13 is localized to the surface of the cell membrane and is anchored by a GPI unit rather than a transmembrane domain. CDH13 lacks the cytoplasmic domain characteristic of other cadherins, so it is not thought to be a cell-cell adhesion glycoprotein. CDH13 acts as a negative regulator of axon growth during neuronal differentiation. CDH13 also protects vascular endothelial cells from apoptosis due to oxidative stress. Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner when connecting cells; cadherins can therefore contribute to the sorting of heterogeneous cell types. They can act as a negative regulator of neuronal cell growth.²²¹
CDH13 is associated with

• Resistance to atherosclerosis
• many types of cancer (CDH13 is hypermethylated there)
• Vacterl association
• Seminoma

Paralog: CDH2

OMIM: Cadherin13 (CDH13) gene

CDH 13 is a candidate gene for ADHD.²²²

• SNP rs7187223, Position 81015234; Intergenic, within 203 kb upstream from CDH13¹⁴⁷
  P: 5.21E-05.
• SNP s11646411, position 81304438; In intron of CDH13¹⁴⁷
  P: 7.40E-06
• SNP rs6565113, position 81665146; intron of CDH13¹⁴⁷
• One study found CDH13 (variant rs8055161) to be one of the 20 most likely among 96 candidate genes¹⁴²

1.116. KIF21B, Kinesin Family Member 21B¶

Other names: KIAA0449, Kinesin-Like Protein KIF21B, DKFZP434J212

The protein KIF21B is a member of the kinesin superfamily. Kinesins are ATP-dependent, microtubule-based motor proteins that are involved in the intracellular transport of membranous organelles.

KIF21B is associated with

• inflammatory bowel diseases (single nucleotide polymorphisms)
• Multiple sclerosis (single nucleotide polymorphisms)

KIF21B is a plus-end-directed microtubule-dependent motor protein with processive activity. KIF21B is involved in the regulation of microtubule dynamics, synapse function and neuronal morphology, including dendritic tree branching and spine formation. KIF21B plays a role in learning and memory. KIF21B is involved in the transfer of the gamma-aminobutyric acid (GABA(A)) receptor to the cell surface.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

Acetylcholine¶

Acetylcholine effect¶

1.32. CHRNA7, alpha-7 neuronal nicotinic acetylcholine receptor¶

The protein neuronal acetylcholine receptor subunit alpha-7 (nAChRα7) is a subunit of certain nicotinic acetylcholine receptors (nAchR).

OMIM: Alpha-7-neuronal nicotinic acetylcholine receptor (CHRNA7) gene

CHRNA 7 is a candidate gene for ADHD.²²³

1.50. CHRNA4, alpha-4-neuronal nicotinic acetylcholine receptor (chromosome 20q13.33)¶

Other names: CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4

OMIM: CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4

The SHRNA4 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.05.³¹⁴⁷ A review also describes an association between CHRNA4 and ADHD²²⁴

1.212. LYPD1, LY6/PLAUR Domain Containing 1¶

Other names: LYPDC1; Ly6/PLAUR Domain-Containing Protein 1; Putative HeLa Tumor Suppressor; MGC29643; PHTS

The protein LYPD1 is thought to act as a modulator of the activity of nicotinic acetylcholine receptors (nAChRs), having acetylcholine receptor binding activity and acetylcholine receptor inhibitory activity.LYPD1 increases in vitro desensitization of the receptor and decreases the affinity for ACh of alpha-4:beta-2-containing nAChRs. LYPD1 may play a role in the intracellular transport of alpha-4:beta-2- and alpha-7-containing nAChRs and inhibits their expression at the cell surface. LYPD1 is involved in post-translational modification: synthesis of GPI-anchored proteins and metabolism of proteins. LYPD1 may be involved in the control of anxiety²²⁵
LYPD1 is associated with

• Arthrogryposis, distal, type 2A
• melanotic medulloblastoma

Paralog: LYPD2

One study found LYPD1 (variant rs7561232) to be one of 96 ADHD candidate genes.¹⁴²

Choline depletion¶

1.40. SLC5A7, CHT1, CHOLINE TRANSPORTER¶

Other names: SOLUTE CARRIER FAMILY 5 (), MEMBER 7; CHT1; Solute Carrier Family 5 (Sodium/Choline Cotransporter), Member 7; High Affinity Choline Transporter 1; HCHT; High Affinity Choline Transporter; Hemicholinium-3-Sensitive Choline Transporter; Solute Carrier Family 5 (Choline Transporter), Member 7; Hemicholinium-3-Sensitive Choline Transporter; CMS20; HMN7A

OMIM: CHT, SOLUTE CARRIER FAMILY 5 (CHOLINE TRANSPORTER), MEMBER 7; SLC5A7

The protein SLC5A7 is a sodium- and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. SLC5A7 transports choline from the extracellular space to presynaptic terminals for the synthesis of acetylcholine. Increased choline uptake results from an increased density of this protein in synaptosomal plasma membranes in response to depolarization of cholinergic terminals. SLC5A7 is a transmembrane transporter that imports choline from the extracellular space into the neuron with high affinity. Choline uptake is the rate-limiting step in acetylcholine synthesis. SLC5A7 is sodium ion- and chloride ion-dependent.²²⁶
SLC5A7 associated with

• Myasthenic syndrome, congenital, 20, presynaptic
• Neuronopathy, distal hereditary motor, type Viia (autosomal dominant distal hereditary motor neuronopathy type VIIA)
• Depression
• ADHD
• Schizophrenia

Paralog: SLC5A2

SLC5A7 - coding variant Ile89Val (rs1013940) has a two to threefold frequency in people with ADHD (n = 100; P = 0.02) and is said to correlate with ADHD-C (OR = 3.16; P = 0.01), while coding variant SNP 3’ (rs333229) is significantly less common in persons with ADHD than in people without ADHD (n = 60; P = 0.004).²²⁷

1.237. SLC44A1, Solute Carrier Family 44 Member 1¶

Other names: CTL1; CD92; CHTL1; CDW92; Solute Carrier Family 44 (Choline Transporter), Member 1; Choline Transporter-Like Protein 1; CDW92 Antigen; CDw92; CD92 Antigen; CONATOC

The protein SLC44A1 is a choline transmembrane transporter. SLC44A1 is involved in choline transport and transmembrane transport. SLC44A1 is present in several cellular components, including the cytosol, mitochondrion and nucleoplasm. SLC44A1 is involved in high-grade gliomas. SLC44A1 is involved in membrane synthesis and myelin production.²²⁸
SLC44A1 is associated with

• Neurodegeneration, beginning in childhood
• Ataxia
• Tremor
• Optic atrophy
• cognitive decline
• postural orthostatic tachycardia syndrome

Paralog: SLC44A3

One study found SLC44A1 (variant rs10991581) to be one of 96 ADHD candidate genes.¹⁴²

Glutamate¶

1.39. GRM1, glutamate receptor metabotropic 1 (chromosome 6p24-3)¶

OMIM:Glutamate receptor metabotropic 1 (GRM1) gene

GRM1 is a candidate gene for ADHD.²²⁹

1.225. GRIK3, Glutamate Ionotropic Receptor Kainate Type Subunit 3¶

Other names: GluK3; GLUR7; Glutamate Receptor Ionotropic, Kainate 3; Excitatory Amino Acid Receptor 5; Glutamate Receptor 7; GluR-7; EAA5; DJ1090M5.1 (Glutamate Receptor, Ionotropic, Kainate 3 (GLUR7)); Glutamate Receptor, Ionotropic, Kainate 3; GluR7a; GluR7; GLR7

GRIK3 is a glutamate receptor. Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiological processes. GRIK3 belongs to the kainate family of glutamate receptors, which consist of four subunits and function as ligand-activated ion channels. It is not certain whether the subunit encoded by this gene is subject to RNA editing like the other two family members (GRIK1 and GRIK2). Kainate receptors have been identified both pre- and postsynaptically. The glutamate receptor GRIK2 binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.²³⁰
GRIK3 is associated with:

• Schizophrenia (a Ser310Ala polymorphism)
• there are contradictory reports about its connection with the pathogenesis of delirium tremens in alcoholics
• Depersonalization disorder

Paralog: GRIK2

One study found GRIK3 (variant rs1032722) to be one of 96 ADHD candidate genes.¹⁴²

1.312. GRIK1, Glutamate Ionotropic Receptor Kainate Type Subunit 1¶

One study investigated the GRIK1 variants rs363504 and rs363538 by measuring GRIK1 expression in peripheral blood.²³¹

• The probands and their fathers had a higher frequency of the genotypes rs363504 ‘CC’ and rs363538 ‘CA’.
• Rs363504 ‘C’ and rs363538 ‘A’ were passed on from the mother to the test subjects.
• Rs363504 ‘TT’ and rs363538 ‘AA’ correlated with higher hyperactivity values.
• Rs363504 ‘TT’ and rs363538 ‘CC’ correlated with an improvement in hyperactivity and inattention with MPH.
• GRIK1 expression was significantly downregulated in the test subjects.

1.34. GRM5, glutamate receptor metabotropic 5 (chromosome 11q14..2 - 14.3) (33, p. 55)¶

OMIM: Glutamate receptor metabotropic 5 (GRM5) gene

GRM5 is a candidate gene for ADHD.²²⁹¹ A study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.38. GRM7, glutamate receptor metabotropic 7 (chromosome 3p26.1)¶

OMIM: Glutamate receptor metabotropic 7 (GRM7) gene

GRM7 is a candidate gene for ADHD.²²⁹

The GMR7 rs3792452 polymorphism influences the response of methylphenidate in children with ADHD.²³²

1.43. SLC9A9, Solute Carrier Family 9 Member A9 (chromosome 3q24)¶

Other names: NHE9; Solute Carrier Family 9, Subfamily A (NHE9, Cation Proton Antiporter 9), Member 9; Sodium/Hydrogen Exchanger 9; Na(+)/H(+) Exchanger 9; FLJ35613; Solute Carrier Family 9 (Sodium/Hydrogen Exchanger), Isoform 9; Solute Carrier Family 9 (Sodium/Hydrogen Exchanger), Member 9; Solute Carrier Family 9 (Sodium/Hydrogen Exchanger); Putative Protein Product Of Nbla00118; Solute Carrier Family 9 Member 9; Sodium/Proton Exchanger NHE9; AUTS16; NHE-9

The SLC9A9 gene encodes a sodium/proton exchanger from the solute carrier 9 protein family. SLC9A9 is localized in the late recycling endosomes and appears to be relevant for the maintenance of cation homeostasis. SLC9A9 is involved in

• electroneutral exchange of protons for Na(+) through membranes
• Excretion of luminal H(+) from the Golgi in exchange for cytosolic cations
• Ion homeostasis of organelles by helping to maintain the unique acidic pH values of the Golgi and post-Golgi compartments in the cell²³³
  SLC9A9 protein counteracts endosomal acidification by alkalizing the system. SLC9A9 controls the tight pH regulation of the endosomal system and clathrin-mediated endocytosis.²³⁴ Consequences SLC9A9 regulates panreceptor recycling.
  Increased SLC9A9 expression in astrocytes of mice²³⁴
• increased surface localization and recycling of the **glutamate transporter **(GLAST)
• increased the uptake of glutamate
  Increased SLC9A9 expression in glioblastoma multiforme (GBM) cell lines²³⁴
• increased the surface localization of the Endothelial Growth Factor Receptor (EGFR)
• increased tumor invasiveness
  Increased SLC9A9 expression²³⁴
• increased internalization and recycling of transferrin receptors in HEK293, brain microvascular endothelial cells and glioma cells
  By regulating transferrin receptor recycling, SLC9A9 plays an important role in iron metabolism.
  **Iron deficiency **causes²³⁴
• increased SLC9A9 expression in human brain microvascular endothelial cells (hBMVECs) that form the blood-brain barrier (BBB)
• increased the **iron uptake **across the blood-brain barrier by
  • Up-regulation of transferrin receptor expression
  • Raising the endosomal pH value
  • increased translocation of TfRs to the hBMVEC membrane
    Amino acid deficiency causes²³⁴
• increased SLC9A9 expression in immortalized hypothalamic neurons and primary cortex cells
  SLC9A9 regulates cellular nutrients and cell metabolism.²³⁴.
  SLC9A9 is associated with:
• ADHD²³⁵²³⁶
• Autism 16²³⁵
  • An ASD nonsense mutation in SLC9A9, R423X, produced no detectable amount of SLC9A9, suggesting an overall loss of SLC9A9 functional networks in ASD. Furthermore, seven of the SLC9A9 interactors are products of known autism candidate genes and 90% of the SLC9A9 interactome overlaps with the SFARI protein interaction network PIN (p < 0.0001), supporting the role of the SLC9A9 interactome in the molecular mechanisms of ASD.
• Colon cancer

Related metabolic pathways:

• Transport of inorganic cations/anions and amino acids/oligopeptides
• Solute:Proton antiporter activity
• Sodium:proton antiporter activity

Paralog: SLC9A7

OMIM: SOLUTE CARRIER FAMILY 9 (SODIUM/HYDROGEN EXCHANGER), MEMBER 9; SLC9A9

One study identified 100 proteins that interact with SLC9A9. These proteins were enriched in known functional pathways for SLC9A9:²³⁶

• Endocytosis
• Protein ubiquitination
• Phagosome pathways
• oxidative stress
• mitochondrial dysfunction
• mTOR signaling
• Cell death
• RNA processing pathways

The ADHD-associated mutation A409P significantly altered the interactions of SLC9A9 with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling.²³⁶
The SLC9A9 gene was identified as a candidate gene for ADHD with p = 0.01 in a 2006 study.³ Another study found SLC9A9 (variant rs7621206) to be one of the 20 most likely among 96 candidate genes.¹⁴² A further study also found SLC9A9 to be the most strongly correlated gene of the genes investigated.¹⁵,

Cannabinoids¶

1.37. CNR1, cannaboid receptor 1 (chromosome 6q14-q15)¶

OMIM: Cannaboid receptor 1 (CNR1) gene

CNR1 is a candidate gene for ADHD.²²²

Traceamine¶

1.42. PNMT, phenylethanolamine, N-methyltransferase (chromosome 17q12)¶

OMIM: Phenylethanolamine, N-methyltransferase gene, PNMT

The PNMT gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.008.³

Glycine¶

1.89. SLC6A9, glycine transporter¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 9

OMIM: SLC6A9, SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 9

Several studies have found a change in the expression of SLC6A9 in ADHD.¹⁰⁶¹³¹

Nitric oxide¶

1.36. NOS1, nitric oxide synthase 1 (chromosome 12q24.22) (87)¶

The protein nitric oxide synthase 1 belongs to the family of nitric oxide synthases that synthesize nitric oxide from L-arginine. Nitric oxide is a biological mediator of neurotransmission, antimicrobial and antitumor activities, among others. Nitric oxide exhibits many properties of a neurotransmitter in the brain and peripheral nervous system. It is involved in

• Neurotoxicity in relation to strokes
• neurodegenerative diseases
• neuronal regulation of smooth muscles, including peristalsis, and penile erection.

OMIM: Nitric oxide synthase 1 (NOS1) gene

Nitric oxide (NO) has been implicated in schizophrenia, ADHD and possibly mood disorders:²³⁷

Genetically determined reduced NO signaling in the PFC is associated with schizophrenia and cognitive problems. NOS1 and its interaction partner NOS1AP play a role here.
Reduced NOS1 expression in the striatum due to a length polymorphism in the NOS1 promoter (NOS1 ex1f-VNTR) correlates with impulsivity.
Associations of NOS1 with mood disorders are possible. NO metabolites in the blood can serve as biomarkers for major depression and bipolar disorders. .

NOS 1 (short allele) is a candidate gene for increased impulsivity and thus for ADHD.²²²²³⁸

Neurotransmitter storage and release¶

1.114. CPLX2, Complexin 2¶

Other names: CPX-2, DKFZp547D155, Complexin II, Complexin-2

CPLX2 is a cytosolic protein and plays a role in the exocytosis of synaptic vesicles. It binds to syntaxin, part of the SNAP receptor, and disrupts it, allowing the release of transmitters. CPLX2 inhibits the formation of synaptic vesicle clusters at the active zone to the presynaptic membrane in postmitotic neurons. CPLX2 promotes a late step in the exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. CPLX2 is involved in the exocytosis of mast cells.²³⁹

CPLX2 is associated with

• Schizophrenia
• Epilepsy, familial temporal lobe, 7.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.177. STXBP6, Syntaxin Binding Protein 6¶

Other names: Amisyn; HSPC156; Syntaxin-Binding Protein 6

STXBP6 forms non-fusogenic complexes with SNAP25 and STX1A and can thereby modulate the formation of functional SNARE complexes and exocytosis.²⁴⁰
STXBP6 is associated with:

• Deafness, autosomal dominant 23
• Deafness, autosomal recessive 35

Paralog: EXOC1

One study found STXBP6 (variant rs17200947)as one of 96 ADHD candidate genes.¹⁴²

1.242. MYO5B, Myosin VB¶

Other names: KIAA1119; Unconventional Myosin-Vb; MYO5B Variant Protein; Myosin-Vb; PFIC10; DIAR2; MVID1

The protein MYO5B could be involved in plasma membrane recycling together with other proteins. MYO5B may be involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling, but not for EGFR degradation. MYO5B is required in a complex with RAB11A and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. MYO5B, together with RAB11A, is involved in CFTR transport to the plasma membrane and in TF (transferrin) recycling in non-polarized cells. MYO5B, together with RAB11A and RAB8A, is involved in the polarization of epithelial cells. MYO5B regulates transcytosis together with RAB25.²⁴¹
MYO5B is associated with

• Diarrhea 2
• Microvillus atrophy, with or without cholestasis
• Microvillus inclusion disease

Paralog: MYO5A

One study found MYO5B (variant rs1787319) to be one of 96 ADHD candidate genes.¹⁴²

1.263. TRAPPC11, Trafficking Protein Particle Complex Subunit 11¶

Other names: C4orf41; Trafficking Protein Particle Complex 11; FLJ12716; Foigr; Gry; Chromosome 4 Open Reading Frame 41; Foie Gras Homolog (Zebrafish); Gryzun Homolog (Drosophila); Foie Gras Homolog; Gryzun Homolog; LGMDR18; LGMD2S; FOIGR; GRY

The protein TRAPPC11 is a subunit of the TRAPP (transport protein particle) tethering complex, which is responsible for intracellular vesicle transport. TRAPPC11 is involved in the early phase of vesicle transport from the endoplasmic reticulum to the Golgi²⁴²
TRAPPC11 is associated with

• Muscular dystrophy
• Limb girdle, autosomal recessive 18
• Intellectual disability-Hyperkinetic Movement Truncal Ataxia Syndrome

Related metabolic pathways:

• Vesicle-mediated transport
• Rab regulation of trafficking.

UniProtKB/Swiss-Prot summary for TRAPPC11 gene
Is involved at a very early stage in the transport from the endoplasmic reticulum to the Golgi apparatus. ( TPC11_HUMAN,Q7Z392 )

One study found TRAPPC11 (variant rs10018951) to be one of 96 ADHD candidate genes.¹⁴²

Brain development¶

1.33. NDE1, Nuclear distribution gene E homologue 1¶

Other names: NudE Neurodevelopment Protein 1; NudE; NDE; Nuclear Distribution Protein NudE Homolog 1; FLJ20101; NUDE; NudE Nuclear Distribution Gene E Homolog 1 (A. Nidulans); NudE Nuclear Distribution E Homolog 1 (A. Nidulans); LIS1-Interacting Protein NUDE1, Rat Homolog; Epididymis Secretory Sperm Binding Protein; NudE Nuclear Distribution Gene E Homolog 1; NudE Nuclear Distribution E Homolog 1; HOM-TES-87; NUDE1; LIS4; MHAC

NDE1 is a member of the Nuclear Distribution E (NudE) family of proteins, localized to the centrosome and required for²⁴³

• Development of the cortex
• Centrosome duplication
• Formation and function of the mitotic spindle
• Organization of the microtubules
• Mitosis
• neuronal migration
• Regulation of the dynein function

NDE1 is associated with

• Microhydranencephaly
• Lissencephaly 4
  • characterized by: Lissencephaly, severe brain atrophy, microcephaly, severe cognitive disabilities

Related signaling pathways:

• Cell cycle
• Mitosis
• EML4
• NUDC in mitotic spindle formation
• identical protein binding
• Microtubule binding

Paralog: NDEL1

OMIM: Nuclear distribution gene E homologue 1 (NDE1) gene

NDE1 is a candidate gene for ADHD.²²³

1.106. MAP1B, Microtubule Associated Protein 1B¶

Other names: PPP1R102, MAP5, Protein Phosphatase 1, Regulatory Subunit 102

The protein MAP1B belongs to the family of microtubule-associated proteins that are thought to be involved in microtubule assembly, which is an essential step in neurogenesis. MAP1B is a precursor polypeptide that is thought to form the final heavy chain of MAP1B and the light chain of LC1 after proteolytic processing. MAP1B knockout mouse studies suggest an important role in the development and function of the nervous system. MAP1B facilitates the tyrosination of alpha-tubulin in neuronal microtubules. Phosphorylated MAP1B appears to play a role in the cytoskeletal changes associated with neurite outgrowth. MMAP1B acts as a positive cofactor in DAPK1-mediated autophagic vesicle formation and membrane blebbing.²⁴⁴
MAP1B is associated with

• Periventricular nodular heterotopia 9
• Deafness, Autosomal Dominant 83

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.107. MOBP, Myelin-Associated Oligodendrocyte Basic Protein¶

The protein MOBP is thought to enable actin and myosin binding activity. MOBP appears to be a structural component of the myelin sheath (possibly by binding the negatively charged acidic phospholipids of the cytoplasmic membrane) and involved in the development of the nervous system. It is probably found in the mitochondrion and is active in the cortical actin cytoskeleton.

MOBP is associated with frontotemporal dementia and cocaine abuse

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁴⁵

1.56. ASTN2, ASTROTACTIN 2 (chromosome 9q33.1)¶

The proteins astrotactin-1 and 2 (ASTN-1 and ASTN-2) are integral membrane-bound perforin-like proteins. They play a crucial role in neurodevelopment. Genetic variations in these proteins are associated with a number of neurodevelopmental disorders and other neurological pathologies, including advanced Alzheimer’s disease. ASTN-2 (unlike ASTN-1) binds inositol triphosphates , suggesting a mechanism for membrane recognition or regulation of its activity by second messengers.

Astrotactin2 (ASTN2) regulates neuronal migration and synaptic strength through the transport and degradation of surface proteins.
The deletion of ASTN2 in copy number variants was detected in:²⁴⁶

• Schizophrenia
• bipolar Disorder
• ASS

whether ASTN2 deficiency affects cognitive and/or emotional behavior and neurotransmission using ASTN2-deficient mice.
Astn2-KO mice showed:²⁴⁶

• no obvious differences in physical characteristics and circadian rhythm
• increased exploratory activity in a new environment
• increased social behavior
• increased impulsivity
• reduced despair and anxiety-like behaviors
• reduced exploration preference for new objects
• reduced dopamine content in the striatum
• increased dopamine and serotonin turnover in the striatum, nucleus accumbens and amygdala
• Thinning of the neuronal cell layers in the hippocampus
• Reduction of neuronal cell bodies in the PFC
• Decrease in spine density and PSD95 protein in hippocampus and PFC

OMIM: ASTROTACTIN 2; ASTN2

• SMP: rs10983238 Position: 118373504; In intron of ASTN2¹⁴⁷
  p: 1.37E-07
  One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.110. TCF4, Transcription Factor 4¶

Other names: BHLHb19, ITF2, Class B Basic Helix-Loop-Helix Protein 19, Immunoglobulin Transcription Factor 2, SL3-3 Enhancer Factor 2, SEF2-1B, E2-2, ITF-2

The TCF4 protein is a basic helix-loop-helix transcription factor. It recognizes an ephrussi box (“E-box”) binding site (“CANNTG”). TCFG4 is widely expressed and may play an important role in the development of the nervous system. TCF4 is involved in the initiation of neuronal differentiation. TCF4 binds to the immunoglobulin enhancer Mu-E5/KE5 motif. TCF4 binds to the E-box in the somatostatin receptor 2 initiator element (SSTR2-INR) and the E-box (5’-CANNTG-3’) to activate transcription.

TCF4 is associated with

• Pitt-Hopkins syndrome
• fuchs’ endothelial corneal dystrophy

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.111. TLL2, Tolloid Like 2¶

Other names: Tolloid-Like Protein 2, EC 3.4.24.19, EC 3.4.24, EC 3.4.24, KIAA0932

The protein TLL2 is an astacin-like zinc-dependent metalloprotease and a member of the metzincin subfamily. TLL2 is a pre-dominant protease and specifically processes pro-lysyl oxidase. TLL2 is required for embryonic development and influences the development of dorsal-ventral patterning and skeletogenesis.

TLL2 is associated with

• Powassan encephalitis
• Louping Ill.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.117. TENM4, Teneurin Transmembrane Protein 4¶

Other names: Ten-M4, KIAA1302, TEN4, ODZ4, Protein Odd Oz/Ten-M Homolog 4, Tenascin-M4

The protein TENM4 plays a role in establishing proper neuronal connectivity during development. TENM4 is involved in the formation of the anterior-posterior axis during gastrulation. TENM4 regulates the differentiation and cellular process formation of oligodendrocytes and the myelination of small diameter axons in the central nervous system (CNS). TENM4 promotes the activation of focal adhesion kinase. TENM4 can act as a cellular signal transmitter.

TENM4 is associated with tremor.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.91. ANK3, ANKYRIN 3¶

Other names: Ankyrin 3; Ankyrin 3, Node Of Ranvier (Ankyrin G); Ankyrin-G; Ankyrin-3; Ankyrin-3, Node Of Ranvier; ANKYRIN-G; MRT37; ANK-3

The scaffold protein ankyrin-3 differs immunologically from the ankyrins ANK1 and ANK2. It is found at the axonal initial section and at the nodes of Ranvier of neurons in the central and peripheral nervous system. Within the nodes of Ranvier, where action potentials are actively transmitted, ANK3 is an intermediate binding partner for neurofascin and voltage-gated sodium channels. ANK3 is required for the normal accumulation of voltage-gated sodium channels at the axon hillock and for the initiation of action potentials.²⁴⁷
In the human brain, ANK3 is found primarily in the cerebellum and, less densely, in the PFC, hippocampus, corpus callosum and hypothalamus. ANK3 plays a central role in regulating the localization of ion channels, membrane transporters, cell adhesion molecules and cytoskeletal proteins. ²⁴⁸
There are connections between ANK3 and dopamine.²⁴⁹²⁵⁰ ANK3 is an essential component of AMPAR-mediated synaptic transmission and maintenance of spine morphology. ANK3 promotes the stability of somatodendritic GABA-ergic synapses in vitro and in vivo by counteracting the endocytosis of GABAA receptors.²⁵¹
ANK3 is expressed by oligodendrocytes, although it is found on the glial rather than the axonal side of the nodes.²⁵² ANK3 regulates the β-catenin/Wnt signaling pathway, which plays a role in bipolar Disorder.²⁵³ A short ANK3 isoform is localized in dendritic spines and regulates NMDA receptor-dependent plasticity.²⁵⁴ ANK3 accumulates in dendritic spines after chronic lithium treatment.²⁵⁵ In bipolar Disorder, ANK3 mRNA is increased in the blood, although no increased expression was found in the brain.²⁵⁶

ANK3 and stress
Prenatal stress influences the interaction of the ANK3 protein with PSD95. ANK3 appears to influence the effects of early childhood stress on the development of psychiatric disorders.²⁵⁷
Heterozygous ANK3+/- mice and mice in which ANK3 was deactivated in the dentate gyrus showed²⁵⁸

• reduced anxiety
  • reversible through chronic lithium administration
• increased reward motivation
  • reversible through chronic lithium administration
    Ank3+/- mice showed an increased sensitivity to chronic stress:
• increased susceptibility to depression-like behaviors
• increased corticosterone levels.

ANK3 is associated with

• PTSD²⁵⁹
• Autism²⁶⁰²⁶¹
• Brugada syndrome, a form of cardiac arrhythmia.
• bipolar Disorder
  • e.g. rs10994336, rs1938526 and rs9804190²⁴⁸
• mental disability.

OMIM: ANK3, ANKYRIN 3

ANK3 is associated with ADHD.¹⁰⁶ A study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.120. ANKS1B, Ankyrin Repeat And Sterile Alpha Motif Domain Containing 1B¶

Other names: AIDA-1, EB-1, Cajalin-2, ANKS2, Ankyrin Repeat And Sterile Alpha Motif Domain-Containing Protein 1B

ANKS1B is a multidomain protein found primarily in the brain and testes. ANKS1B interacts with the amyloid beta protein precursor (AbetaPP) and may play a role in normal brain development and in the development of Alzheimer’s disease. Isoform 2 may be involved in the regulation of nucleoplasmic coilin-protein interactions in neuronal and transformed cells. Isoform 3 may regulate global protein synthesis by altering the number of nucleoli. Isoform 4 may play a role as a modulator of APP processing. Overexpression may downregulate APP processing.²⁶²

ANKS1B is associated with

• Alzheimer’s disease
• acute lymphocytic pre-B-cell leukemia

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.233. EPHA7, EPH Receptor A7¶

Other names: HEK11; Ephrin Type-A Receptor 7; EPH Homology Kinase 3; EPH-Like Kinase 11; EC 2.7.10.1; Hek11; EHK-3; EHK3; EK11; Receptor Protein-Tyrosine Kinase HEK11; Tyrosine-Protein Kinase Receptor EHK-3; Eph Homology Kinase-3; EC 2.7.10; EphA7

The EPHA7 protein belongs to the ephrin receptor subfamily of the protein tyrosine kinase family. EPH and EPH-related receptors are involved in the mediation of developmental events, particularly in the nervous system. EPH subfamily receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and two fibronectin type III repeats. The ephrin receptors are categorized into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin A and ephrin B ligands. EPHA7 is a receptor tyrosine kinase that promiscuously binds GPI-anchored ephrin A-family ligands located on neighboring cells, resulting in contact-dependent bidirectional signaling into neighboring cells.
The signaling pathway downstream of the receptor is referred to as forward signaling, while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin A ligands, EFNA5 is a cognate/functional ligand for EPHA7, and their interaction regulates brain development by modulating cell-cell adhesion and repulsion. EFNA5 has a repulsive effect on axons and is involved, for example, in the guidance of corticothalamic axons and in the correct topographic mapping of retinal axons to the colliculus. EPHA7 may also regulate brain development through caspase (CASP3)-dependent proapoptotic activity. Forward signaling may lead to activation of components of the ERK pathway, including MAP2K1, MAP2K2, MAPK1 and MAPK3, which are phosphorylated upon activation of EPHA7.²⁶³
EPHA7 is associated with

• Brachydactyly-syndactyly syndrome
• Brachydactyly, type A4
• various carcinomas with increased gene expressionin

Paralog: EPHA5

One study found EPHA7 (variant rs16870710) as one of 96 ADHD candidate genes.¹⁴²

1.299. SEMA6D, Semaphorin 6D¶

Other names: KIAA1479; Sema Domain, Transmembrane Domain (TM), And Cytoplasmic Domain, (Semaphorin) 6D; Semaphorin-6D; FLJ11598

SEMA6D is a vertebrate class 6 transmembrane semaphorin. Semaphorins are a large family that includes both secreted and membrane-associated proteins, many of which are involved as inhibitors or chemorepellents in axon pathfinding, fasciculation and branching, and target selection. All semaphorins have a semaphorin domain (Sema) and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular part. Additional sequence motifs at the C-terminus of the semaphorin domain allow classification into different subfamilies. Transmembrane semaphorins as well as secreted semaphorins can act as repulsive axon guidance markers. SEMA6D acted in vitro on neurons of the dorsal root ganglion (DRG). SEMA6D may be a stop signal for DRG neurons in their target areas and possibly for other neurons as well. SEMA6D may also be involved in the maintenance and remodeling of neuronal connections.²⁶⁴
SEMA6D is associated with

• Cone-Rod dystrophy 10
• Kallmann syndrome

Related signal paths:

• Semaphorin interactions
• Development of the nervous system
• Signal receptor activity
• Semaphorin receptor binding

Paralog: SEMA6A

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁷⁰

1.63. NAV2, NEURON NAVIGATOR 2 (chromosome 11p15.1)¶

Other names: APC down-regulated 1; FLJ10633; FLJ11030; FLJ23707; HELAD1; KIAA1419; POMFIL2; RAINB1, helicase, pore membrane and/or filament interacting like protein 2; Retinoic acid inducible gene in neuroblastoma 1;

The protein Neuron Navigator 2 (NAV2) is a member of the neuron navigator protein family. NAV2 is widely distributed in the central nervous system (CNS), especially in the developing cerebellum (verebellum). NAV2 is critical for cytoskeletal dynamics and neurite outgrowth²⁶⁵
Nav2 is associated with

• Cerebellar hypoplasia with abnormal folding due to impaired axonal outgrowth
• Corpus callosum hypo-dysgenesis
• Agenesis of the olfactory bulbs
• cellular migration deficits
• NAV2 abnormalities are usually lethal²⁶⁵

OMIM: NEURON NAVIGATOR 2

The SNP rs874426 position: 19526139; In intron of NAV2 was identified as an ADHD gene candidate with p: 3.75E-06.¹⁴⁷

1.119. CNNM2, Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2¶

Other names: ACDP2, Ancient Conserved Domain-Containing Protein 2, Metal Transporter CNNM2, Cyclin M2, Cyclin-M2, HOMGSMR, HOMG6

The protein CNNM2 is a transporter for divalent metal cations in the Order of priority Mg(2+) > Co(2+) > Mn(2+) > Sr(2+) > Ba(2+) > Cu(2+) > Fe(2+). CNNM2 is a member of the family of proteins that contain ancient conserved domains. Members of this protein family contain a cyclin box motif and have structural similarity to cyclins. CNNM2 may play an important role in magnesium homeostasis by mediating epithelial transport and renal reabsorption of Mg2+. CNNM2 plays a role in brain development and neurological function.

CNNM2 is associated with

• Hypomagnesemia
• Renal and hypomagnesemia
• Seizures
• mental retardation
• Schizophrenia²⁶⁶
• Depression²⁶⁶

CNNM2 is one of the three most important genes that interact with AS3MT. AS3MT rs7085104 is associated with a change in striatal dopamine synthesis capacity.⁶

One study found CNNM2 to be one of the 51 most likely gene candidates for ADHD.⁷

1.324. DLG4 / PSD-95¶

Other names: Discs Large MAGUK Scaffold Protein 4; SAP-90; PSD95; SAP90; PSD-95; Synapse-Associated Protein 90; Discs Large Homolog 4; Discs Large Homolog 4; Discs, Large Homolog 4 (Drosophila); Post-Synaptic Density Protein 95; Postsynaptic Density Protein 95; Tax Interaction Protein 15; MRD62; DLG-4

The DLG4 gene encodes the protein PSD-95, which is required for the maturation of glutamatergic synapses. It is recruited to NMDA receptor and potassium channel clusters and heteromultimerizes with DLG2, another MAGUK protein. These two MAGUK proteins can interact at postsynaptic sites and form a multimeric scaffold for the clustering of receptors, ion channels and associated signaling proteins.²⁶⁷

DLG4 is associated with:

• Intellectual development disorder, autosomal dominant 62
• Dlg4-related synaptopathy

Related signaling pathways:

• Unblocking of NMDA receptors
• Glutamate binding
• Glutam activation
• RAF/MAP kinase cascade

Paralog: DLG1.

Young neurons are far more capable of learning than older neurons. The maturation of excitatory synapses into “older” synapses, which lead to exhibitory (excitatory) neurons that are less capable of learning, is controlled by PSD-93 and PSD-95 (PSD: Postsynaptic Density Proteins), among others.
The synapses of young nerve cells only have active NMDA glutamate receptors, but not active AMPA glutamate receptors. This means that only very high glutamate levels can activate young neurons. PSD-95 is required for the maturation of neurons. This activates AMPA receptors, whereby neurons also react to lower glutamate levels. A knockout of PSD-95 made neurons as plastic as in 4-week-old wild-type animals and reduced the number of binoluclear cells.²⁶⁸ In contrast, PSD-93 prevents neurons from maturing and losing their plasticity.²⁶⁹

The DRD4 gene variant with 7 alleles (DRD4.7), which is more common in ADHD, caused a reduced PSD-95 level in the PFC in vitro (compared to the DRD4-4 variant, which is rarer in ADHD).²⁷⁰ This could possibly explain the delayed brain maturation typical of ADHD.
Wistar rat pups that received rotenone (an inhibitor of mitochondrial complex I) postnatally showed hyperlocomotion, deficits in social interaction and aversive contextual memory (symptoms of ADHD, ASD and schizophrenia, all of which are linked to the dopaminergic system). As adult animals, they showed changes in CBP and CREB levels, a decrease in mitochondrial biogenesis and Nrf1 expression, as well as altered expression of Rest, Mecp2 and the synaptic proteins PSD-95, synaptotagmin-1 and synaptophysin.²⁷¹
PSD-95 contributes to the formation of a ternary complex of calcyon with the dopamine D1 receptor and thus co-regulates DRD1 trafficking.²⁷²
A defect in the DLG-4 gene (which encodes PSD-95) causes a neuronal disorder with global developmental delay, mental retardation and ADHD and ASD symptoms.²⁷³²⁷⁴

1.325. FEZ1¶

Other names: Fasciculation And Elongation Protein Zeta 1; Zygin I; UNC-76; Fasciculation And Elongation Protein Zeta-1; Zygin-1
Do not confuse with FEZF1.

FEZ1 (Fasciculation And Elongation Protein Zeta 1) encodes a protein.
FEZ1 is associated with:

• Lissencephaly 1
• Schizophrenia

Related signal paths:

• Cytoskeletal Signaling
• Neuroscience
• Binding of obsolete protein N-terminus
• Binding of gamma-tubulin

Paralog: FEZ2.

FEZ1 is possibly involved in axonal growth. FEZ1 can restore partial locomotion and axonal fasciculation of C. elegans unc-76 mutants in germline transformation experiments. FEZ1 may be involved in the transport of mitochondria and other cargo along microtubules.²⁷⁵

The FEZ1 gene is specifically expressed in the nervous system and is most strongly expressed during neurodevelopment. FEZ1 is involved in various processes of neurodevelopment, such as:²⁷⁶

• Neurite extension
• dendritic arborization
• axonal transport
• neuronal migration

FEZ1 knockout mice show:²⁷⁶

• Hyperactivity²⁷⁷
• Impulsiveness
• Tyrosine hydroxilase expression reduced in midbrain and brainstem
• Dopamine and noradrenaline levels and their metabolites in the nucleus accumbens and PFC reduced
• MPH and guanfacine caused
  • Hyperactivity and impulsivity improved
  • Dopamine and noradrenaline levels restored in the nucleus accumbens and PFC
  • Tyrosine hydroxilase expression increased

Growth factors, neurogenesis¶

1.25. NTF3, neurotrophin 3 (chromosome 12p13.31)¶

Other names: Neurotrophin-3; NGF2; Nerve Growth Factor; Neurotrophic Factor; NGF-2; HDNF; NT-3; NT3

The protein NTF3 belongs to the family of neurotrophins that control the survival and differentiation of mammalian neurons. NTF3 is closely related to nerve growth factor and brain-derived neurotrophic factor. NTF3 may be involved in the maintenance of the adult nervous system and may influence the development of neurons in the embryo when expressed in the human placenta. NTF3-KO mice exhibit severe limb movement disorders. The mature peptide of this protein is identical in all mammals studied, including human, pig, rat and mouse.UniProtKB/Swiss-Prot summary for NTF3 appears to promote the survival of visceral and proprioceptive sensory neurons.²⁷⁸
NTF3 is associated with

• Hypochondriasis
• diabetic polyneuropathy

Related signaling pathways:

• Apoptotic Pathways in Synovial Fibroblasts
• GPCR Pathway
• Signal receptor binding
• chemoattractive activity

Paralog: NGF

OMIM: Neurotrophin-3 (NTF3) gene

NTF3 is a candidate gene for ADHD.¹¹⁴⁷

1.71. NTF4, NEUROTROPHIN 4 (chromosome 19q13.33)¶

Other names: NT-4/5; GLC1O; NTF5; Neurotrophin 5 (Neurotrophin 4/5); Neurotrophic Factor 4; Neutrophic Factor 4; Neurotrophin-4; Neurotrophin-5; NT-4; NT-5; Neurotrophic Factor 5; GLC10; NT4; NT5

The protein NTF4 is a member of a family of neurotrophic factors, the neurotrophins, which control the survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and is less affected by environmental signals. While knock-outs of other neurotrophins, including nerve growth factor, brain-derived neurotrophic factor and neurotrophin 3, are lethal during early postnatal development, NTF5-KO mice show only minor cellular deficits and develop normally into adulthood. NTF4 is a target-derived survival factor for peripheral sensory sympathetic neurons.²⁷⁹
NTF4 is associated with

• Glaucoma 1, open angle, O
• Open-angle glaucoma

Related signaling pathways:

• Differentiation pathway of pluripotent stem cells
• apoptotic signaling pathway in synovial fibroblasts
• Binding of signal receptors
• Binding of neurotrophin p75 receptors

Paralog: BDNF

OMIM: NEUROTROPHIN 4; NTF4

NTF4 is a candidate gene in ADHD.¹⁴⁷

1.26. BDNF, brain-derived neurothropic factor (chromosome 11p14.1) (X)¶

OMIM: Brain-derived neurothropic factor (BDNF) gene

BDNF is a candidate gene for ADHD.¹¹⁴⁷

The BDNF gene is involved in the formation of the dopamine D3 receptor (see OMIM on DRD3) in the nucleus accumbens during development and adolescence.
In children with ADHD, poorer performance on the Stroop test of executive functions correlated BDNF GG genotype rs2030324.²⁸⁰ One study found a positive correlation between the BDNF gene polymorphism rs10835210 and ADHD-HI and a negative correlation of BDNF-rs12291186 with one or both mutant alleles with ADHD.²⁸¹

1.27. BAIAP2, Brain-specific angiogenesis inhibitor 1-associated protein¶

OMIM: Brain-specific angiogenesis inhibitor 1-associated protein (BAIAP2) gene

BAIAP2 is a candidate gene for ADHD.¹²⁸²

1.70. NGF, NERVE GROWTH FACTOR (chromosome 1p13.2)¶

OMIM: NERVE GROWTH FACTOR

Source¹⁴⁷

1.72. GDNF, GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR (chromosome 5p13.2)¶

OMIM: GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; GDNF

Source¹⁴⁷

1.54. UNC5, C. ELEGANS, HOMOLOG OF, B; UNC5B (chromosome 10q22.1)¶

UNC-5 is a receptor for netrins. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion to guide axons, while the other netrin receptor, UNC-40, attracts axons to the source of netrin production.

OMIM: UNC5, C. ELEGANS, HOMOLOG OF, B; UNC5B

• SNP: rs16928529 Position: 72652991; In intron of UNC5B¹⁴⁷
  p: 3.90E-06

1.61. GPC6, GLYPICAN 6 (chromosome 13q31.3-q32.1)¶

Glypicans are a family of glycosylphosphatidylinositol-anchored heparan sulfate proteoglycans. Glypicans are involved in the control of cell growth and cell division. Glypican 6 is a putative cell surface coreceptor for growth factors, extracellular matrix proteins, proteases and anti-proteases.
Mutations of glypican 6 are associated with omodysplasia 1.

OMIM: GLYPICAN 6; GPC6

• SNP: rs7995215 Position: 93206507; In intron of GPC6¹⁴⁷
  P: 1.35E-08
  One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.232. CNTN5, Contactin 5¶

Other names: HNB-2; NB-2; Neural Recognition Molecule NB-2; Contactin-5; Neural Adhesion Molecule; HNB-2s

The protein CNTN5 is a member of the immunoglobulin superfamily and the contactin family. Contactins mediate cell surface interactions during the development of the nervous system. CNTN5 is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. CNTN5 may play a role in the formation of axon connections in the developing nervous system. CNTN5 promotes neurite outgrowth in cerebral cortical neurons but not in hippocampal neurons. CNTN5 is probably involved in neuronal activity in the auditory system.²⁸³
CNTN5 is associated with

• Coffin-Siris syndrome 6
• Chromosome 3Pter P25 deletion syndrome

Paralog: CNTN4

One study found CNTN5 (variant rs2515376) to be one of 96 ADHD candidate genes.¹⁴²

Cell development¶

1.298. POC1B, POC1 Centriolar Protein B¶

Other names: TUWD12; WDR51B; POC1 Centriolar Protein Homolog B; WD Repeat-Containing Protein 51B; Proteome Of Centriole Protein 1B; FLJ14923; POC1 Centriolar Protein Homolog B (Chlamydomonas); WD Repeat Domain 51B; CORD20; PIX1; Pix1

POC1B encodes one of the two POC1 proteins found in humans. POC1 proteins contain an N-terminal WD40 domain and a C-terminal coiled-coil domain and are part of centrosomes. They play an important role in the formation of the basal body and cilia. POC1B plays an important role in centriol formation and/or stability and cilia genesis. POC1B is involved in early steps of centriole duplication as well as in the later steps of centriole length control. POC1B acts together with POC1A to ensure the integrity of the centriole and the correct formation of the mitotic spindle. POC1B is required for primary cilia formation, cilia length and also cell proliferation. POC1B is required for the integrity of the retina.²⁸⁴
POC1B is associated with

• Cone-Rod Dystrophy 20
• Cone-Rod Dystrophy 2

Related signal paths:

• Ciliopathies

Paralog: POC1A

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁷⁰

1.62. CTNNA2, CATENIN ALPHA-2 (chromosome 2p12)¶

Other names: CAP-R; CT114; Catenin (Cadherin-Associated Protein), Alpha 2; Cadherin-Associated Protein, Related; Alpha-Catenin-Related Protein; Cancer/Testis Antigen 114; Alpha-N-Catenin; Catenin Alpha-2; CAPR; Alpha N-Catenin; CDCBM9; CTNR

The protein CTNNA2 enables actin filament binding activity. It is involved in the following functions:

• Inhibition of actin nucleation mediated by the Arp2/3 complex and Arp2/3-mediated actin polymerization Thus, CTNNA2 suppresses excessive actin branching, which would impair the growth and stability of neurites.²⁸⁵
• Regulation of neuron migration / development of the nervous system
• Regulation of the development of neuron projections
• Link between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system.
• Regulation of cortical neuronal migration and neurite outgrowth.
• Regulation of morphological plasticity of synapses and lamination of cerebellum and hippocampus during development.
• Control of startle modulation.

CTNNA2 is involved in the following disorders:

• complex cortical dysplasia with other brain malformations 9 (CDCBM9)
• Hereditary Breast Ovarian Cancer Syndrome

OMIM: CATENIN, ALPHA-2

• SNP: rs13395022 Position: 79735768; In intron of CTNNA2¹⁴⁷
  p: 9.68E-06

Circadian rhythm¶

The circadian clock, an internal timing system, regulates various physiological processes by generating approximately 24-hour circadian rhythms in gene expression, which translate into rhythms in metabolism and behavior. The circadian system is an important regulator of a variety of physiological functions such as metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular and renal functions. The circadian system consists of two main components: the central clock, which is located in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks, which are found in almost all tissues and organ systems. Both the central and peripheral clocks can be reset by environmental stimuli, also known as zeitgebers. The predominant zeitgeber for the central clock is light, which is perceived by the retina and transmitted directly to the SCN. The central clock controls the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related signals, so that all clocks are synchronized to the external light-dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to reach a peak in protein expression every 24 hours to control when a particular physiological process is most active in relation to the solar day. Transcription and translation of key clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) play a crucial role in rhythm formation, while delays due to post-translational modifications (PTM) are important for determining the period (tau) of rhythms (tau refers to the period of a rhythm and is the temporal length of a complete cycle). A diurnal rhythm is synchronized with the day-night cycle, while the ultradian and infradian rhythms have a shorter and longer period than 24 hours, respectively. Disorders of circadian rhythms contribute to the pathology of cardiovascular disease, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular mechanism of the circadian clock. The transcription factors CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2 form the positive link of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in important metabolic processes) that carry E-box elements (5’-CACGTG-3’) in their promoters. The major clock genes: PER1/2/3 and CRY1/2, which are transcriptional repressors, form the negative link of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer by inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates the nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and activate and repress ARNTL/BMAL1 transcription, respectively.²⁸⁶

1.29. CLOCK, Clock Circadian Regulator (chromosome 4q12) (x)¶

Other names: BHLHe8; Circadian Locomoter Output Cycles Protein Kaput; KIAA0334; KAT13D; Class E Basic Helix-Loop-Helix Protein 8; EC 2.3.1.48; Circadian Locomoter Output Cycles Kaput Protein; Clock (Mouse) Homolog; Clock Homolog (Mouse); EC 2.3.1.48’); Clock Homolog; BHLHE8; HCLOCK

The CLOCK protein plays a central role in the regulation of circadian rhythms. CLOCK encodes a transcription factor of the bHLH family (basic helix-loop-helix) and has DNA-binding histone acetyltransferase activity. CLOCK forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of period (PER1, PER2, PER3) and cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting with CLOCK/ARNTL complexes in a feedback loop. CLOCK regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. CLOCK plays an important role in the homeostatic regulation of sleep. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and genes involved in glucose and lipid metabolism. CLOCK promotes the rhythmic opening of chromatin and regulates the DNA accessibility of other transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5’-CACGTGA-3’, which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence(CLOCK; GeneCards.org))
Clock acts as a transcriptional suppressor of tyrosine hydroxylase, which is involved in dopamine synthesis.²⁸⁷
CLOCK is associated with

• delayed sleep phase disorder
• Narcolepsy
• Behavioral changes in certain populations
• Obesity
• metabolic syndrome

Paralog: NPAS2

OMIM: Circadian Locomotor Output Cycles Protein Kaput (CLOCK) gene

CLOCK is a candidate gene for ADHD.¹
The gene variants of the AA and AG genotypes of rs1801260 correlated significantly with ADHD. Similarly, the Rs1801260 polymorphism is a risk factor for ADHD.²⁸⁸ Increased expression of CLOCK, PER1, lncRNA HULC and lncRNA UCA1 correlated with
evening chronotype, problems falling asleep and staying asleep, disorders of the sleep-wake transition and excessive sleepiness in ADHD. There was no significant correlation between individual genes and certain sleep parameters.²⁸⁹

1.261. PER1, Period Circadian Regulator 1 (chromosome 2q37.3)¶

Other names: RIGUI; PER; Period Circadian Protein Homolog 1; Circadian Clock Protein PERIOD 1; Period Circadian Clock 1; HPER1; Circadian Pacemaker Protein RIGUI; Circadian Pacemaker Protein Rigui; Period, Drosophila, Homolog Of; Period (Drosophila) Homolog 1; Period Homolog 1 (Drosophila); Period Homolog 1; KIAA0482; HPER

PER1 belongs to the period gene family and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. The genes of this family encode components of the circadian rhythms of locomotor activity, metabolism and behavior.
PER1 is upregulated by CLOCK/ARNTL heterodimers, but then suppresses this upregulation in a feedback loop by PER/CRY heterodimers that interact with CLOCK/ARNTL. PER1 is a transcriptional repressor that forms a core component of the circadian clock.
PER1 regulates the expression of circadian target genes at the post-transcriptional level, but may not be required for repression at the transcriptional level. PER1 controls PER2 protein decay. PER1 represses CRY2, preventing its repression of CLOCK/ARNTL target genes such as FXYD5 and SCNN1A in the kidney and PPARA in the liver. In addition to its involvement in the maintenance of the circadian clock, PER1 has an important function in the regulation of various processes. PER1 is involved in the repression of transcriptional activity induced by the glucocorticoid receptor NR3C1/GR by reducing the association of NR3C1/GR with glucocorticoid response elements (GREs) through ARNTL:CLOCK. PER1 plays a role in modulating the neuroinflammatory state by regulating the release of inflammatory mediators, such as CCL2 and IL6. In spinal astrocytes, PER1 inhibits the MAPK14/p38 and MAPK8/JNK-MAPK cascades and the subsequent activation of NFkappaB. PER1 coordinately regulates the expression of several genes involved in the regulation of renal sodium reabsorption. PER1 can act as a gene- and tissue-specific activator of gene expression; in the kidney, PER1 increases the expression of WNK1 and SLC12A3 in cooperation with CLOCK. PER1 modulates the hair follicle cycle. PER1 represses CLOCK-ARNTL/BMAL1-induced transcription of BHLHE40/DEC1.²⁸⁶
PER1 is associated with

• Corticosteroid-Binding Globulin Deficiency
• Rem Sleep Behavior Disorder
• Cancer

Related signal paths:

• Melatonin metabolism and effects
• circadian clock
• Binding of transcription factors
• sequence-specific DNA binding in the cis-regulatory region of RNA polymerase II

Paralog: PER2

The PER2 gene was identified as a candidate gene for ADHD in a 2008 study. It is thought to correlate with general ADHD symptoms.¹⁵ Increased expression of CLOCK, PER1, lncRNA HULC and lncRNA UCA1 correlated with
evening chronotype, problems falling asleep and staying asleep, disorders of the sleep-wake transition and excessive sleepiness in ADHD. There was no significant correlation between individual genes and certain sleep parameters.²⁸⁹

1.47. PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2 (chromosome 2q37.3)¶

OMIM: PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2

The PER2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.017.³

1.73. VASOACTIVE INTESTINAL PEPTIDE RECEPTOR 2; VIPR2 (chromosome 7q36.3)¶

VIPR2 and VIPR1 (192321) encode receptors for the neuropeptide vasoactive intestinal peptide (VIP; 192320) and also bind pituitary adenylate cyclase activating polypeptide (PACAP; 102980) with the same affinity as VIP.

The human VIP2 receptor binds to PACAP38, PACAP27, VIP and heldermin, each of which activates adenylate cyclase. GTP inhibits the binding of the peptide.

Food intake triggers a neuronal signal from the gut with antimicrobial and metabolic responses. This signal is controlled by innate lymphoid cells type 3 (ILC3). Food intake rapidly activates a population of intestinal neurons that produce VIP. Projections of VIP-producing neurons in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIPR2. VIPR2 inhibits IL22 synthesis. Consequences are that the level of antimicrobial peptides derived from epithelial cells is reduced, while the expression of lipid-binding proteins and transporters is increased. Thus, during food consumption, activation of VIP-producing neurons promotes the growth of segmented filamentous bacteria associated with the epithelium and increases lipid absorption. This establishes a nutrition- and circadian-regulated dynamic neuroimmune circuit in the gut that moderates between innate immune protection mediated by IL22 and the efficiency of nutrient absorption.

Rare copy number variants (CNVs) of VIPR2 are associated with schizophrenia-
Microduplications of 7q36.3 correlated with increased VIPR2 transcription and increased cyclic AMP signaling.

Vipr2 -/- mice (VPR2-KO mice) are unable to maintain normal circadian rhythms of rest/activity behavior and show no circadian expression of the central clock genes Per1 (602260), Per2 (603426) and Cry1 (601933) and the clock-controlled gene encoding arginine vasopressin (AVP; 192340) in the suprachiasmatic nuclei. In addition, VPR2-KO mice showed no acute induction of Per1 and Per2 by nocturnal illumination.

OMIM: VASOACTIVE INTESTINAL PEPTIDE RECEPTOR 2; VIPR2

Source⁴⁹

1.79. KAT2B, LYSINE ACETYLTRANSFERASE 2B¶

The protein KAT2B (lysine acetyltransferase 2B) is involved in²⁹⁰

• Signaling pathway of apoptotic pathways in synovial fibroblasts
• Signaling pathway of the regulation of activated PAK-2p34 by proteasome-mediated degradation
• Protein kinase binding
• KAT2B is a histone acetyltransferase (HAT) and thus increases transcriptional coactivator activity
• Has significant histone acetyltransferase activity with core histones (H3 and H4) and also with nucleosome core particles
• Also acetylates non-histone proteins such as ACLY, MAPRE1/EB1, PLK4, RRP9/U3-55K and TBX5
• Inhibits cell cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A
• Acts as a circadian transcriptional coactivator that enhances the activity of circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers
• Acetylation of TBX5, thereby involvement in the development of the heart and limbs
  • Acetylation regulates the nucleocytoplasmic shuttling of TBX5
• inhibits centrosome amplification by mediating the acetylation of PLK4
• Acetylates RRP9/U3-55K, a central subunit of the U3 snoRNP complex, and thus impairs the processing of pre-rRNA
• Acetylates MAPRE1/EB1 and thus promotes dynamic kinetochore-microtubule interactions in early mitosis
• Acetylated spermidine
• is recruited by the viral protein Tat during HIV-1 infection. Regulates the transactivating activity of Tat and can contribute to the induction of chromatin remodeling of proviral genes.

KAT2B is associated with diseases:

• Holt-Oram syndrome
• spinocerebellar ataxia 7

OMIM: KAT2B, LYSINE ACETYLTRANSFERASE 2B

KAT2B is a candidate gene for ADHD.²⁹¹

1.84. CADM1, CELL ADHESION MOLECULE 1 (TSLC1, IGSF4); CADM2, ELL ADHESION MOLECULE 2¶

Other names: SYNCAM; IGSF4A; NECL2; Tumor Suppressor In Lung Cancer 1; Necl-2; RA175; IGSF4; TSLC1; ST17; BL2; Spermatogenic Immunoglobulin Superfamily; Immunoglobulin Superfamily Member 4; Synaptic Cell Adhesion Molecule; Nectin-Like Protein; Nectin-Like 2; SYNCAM1; TSLC-1; Immunoglobulin Superfamily, Member 4; TSLC1/Nectin-Like 2/IGSF4; STSLC-1; SynCAM1; SgIGSF; NECL-2; SgIgSF; SynCAM; IgSF4

The protein CADM1 enables signal receptor binding activity. CADM1 is involved in:²⁹²

• Cell recognition
• positive regulation of cytokine production
• promotes the cytotoxicity of natural killer cells (NK)
• promotes the secretion of interferon-gamma (IFN-gamma)
• Organization of cell adhesion (cell connections).
• relevant for the survival of mast cells
• mediates binding to and communication with nerves in mast cells
• acts as a synaptic cell adhesion molecule
• plays a role in the formation of dendritic spines and in synapse formation
• May be involved in neuronal migration, axon growth, pathfinding and fasciculation on the axons of differentiating neurons
• is located in the plasma membrane
• is used for breast cancer and prostate cancer.

SynCAM1 is an adhesion molecule involved in synaptic differentiation and organization. SynCAM1 is also expressed in astroglial cells, where it mediates adhesive communication between astrocytes and between glia and neurons. In astrocytes, SynCAM1 is functionally associated with erbB4 receptors, which are involved in the control of both neuronal/glial development and mature neuronal and glial function.²⁹³

CADM1 is associated with:

• Cervical Carcinoma In Situ
• Retroperitoneal fibrosis

Paralog: CADM2
Certain gene variants of the CADM2 gene are associated with hyperactivity.²⁹⁴

OMIM: CADM1, CELL ADHESION MOLECULE 1

In a study, the CADM1 rs10891819 genotype (T alleles) correlated negatively with errors in the Stroop test, thus positively with inhibition ability and therefore ADHD-protective.²⁹⁵ Inhibition of CADM1 in astrocytes in mice causes ADHD symptoms. The mice also showed daytime (during the light period of the light cycle), suggesting that their diurnal pattern of locomotor and/or sleep activity was impaired. The mice also showed consistent aimless exploratory behavior in familiar surroundings, as well as increased impulsivity and aggeressiveness (tendency to jump out of the cage when the cage lid was opened, and to attack other animals or the person who opened the cage without provocation).²⁹³

CRY1¶

People with ADHD (often?) carry a mutation in the central circadian gene CRY1 (c. 1657 + 3A > C), which leads to a deletion of exon 11 in the CRY1 protein (CRY1Δ11), causing them to show typical ADHD symptoms.
Cry1Δ11 (c. 1717 + 3A > C) mice show ADHD-like symptoms:²⁹⁶

• Hyperactivity
• Impulsiveness
• Learning deficits
• Memory deficits
• hyperactive cAMP signaling pathway in the nucleus accumbens
• upregulated c-Fos, mainly localized in dopamine D1 receptor-expressing medium spiny neurons (DRD1-MSNs) in the NAc
• increased neuronal excitability of DRD1-MSNs in the nucleus accumbens
• the CRY1Δ11 protein, unlike the WT CRY1 protein, could not mechanistically interact with the Gαs protein and inhibit DRD1 signaling
• the DRD1 antagonist SCH23390 normalized most ADHD-like symptoms

Immune system¶

1.57. CSMD2, CUB AND SUSHI MULTIPLE DOMAINS 2 (chromosome 1p35.1)¶

The protein CSMD2 appears to be involved in controlling the complement cascade of the immune system. It could serve as a tumor suppressor for colorectal cancer. Genetic defects are associated with schizophrenia.

OMIM: CUB AND SUSHI MULTIPLE DOMAINS 2

• SNP: rs2281597 Position: 34132445; In intron of CSMD2¹⁴⁷
  p: 5.41E-07
  One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.112. TRIM26, Tripartite Motif Containing 26¶

Other names: RNF95, ZNF173, Tripartite Motif-Containing Protein 26, Zinc Finger Protein 173

The TRIM26 protein is a member of the TRIM family (tripartite motif). The TRIM motif comprises three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2 as well as a coiled-coil region. TRIM26 is found in cytoplasmic bodies. The RING domain indicates that TRIM26 may have DNA-binding activity. TRIM26 is an E3 ubiquitin-protein ligase that regulates IFN-beta production and antiviral response downstream of various DNA-encoded pattern recognition receptors (PRRs). TRIM26 promotes IRF3 core ubiquitination and proteasomal degradation. TRIM26 links TBK1 and NEMO during the innate response to viral infection, leading to activation of TBK1.

TRIM26 is associated with neural tube defects.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.210. MYO1G, Myosin IG¶

Other names: Minor Histocompatibility Antigen HA-2; Unconventional Myosin-Ig; HA-2; HA2; Myosin-Ig; HLA-HA2; MHAG

The MYO1G protein is a class I myosin associated with the plasma membrane and is abundant in T and B lymphocytes and mast cells.
MYO1G is an unconventional myosin that is required during the immune response for the recognition of rare antigen-presenting cells by regulating the migration of T cells. Unconventional myosins are actin-based motor molecules with ATPase activity and are used for intracellular movement.
MYO1G acts as a regulator of T cell migration by generating a membrane tension that enforces the cell’s own meandering search, thereby enhancing the recognition of rare antigens during lymph node surveillance, enabling pathogen eradication. MYO1G is also required in B cells, where it regulates various membrane/cytoskeleton-dependent processes. MYO1G is involved in phagocytosis with the Fc-gamma receptor.
MYO1G forms the minor histocompatibility antigen HA-2. In more general terms, minor histocompatibility antigens (mHags) are immunogenic peptides that, when complexed with MHC, can trigger an immune response when recognized by specific T cells. The peptides are derived from polymorphic intracellular proteins that are cleaved by the normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and their expression on the cell surface can trigger a T-cell response and thereby cause graft rejection or graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation from HLA-identical sibling donors.²⁹⁷
MYO1G is associated with

• Graft-versus-host disease. This is a common complication after bone marrow transplantation (BMT) due to a mismatch of the minor histocompatibility antigen in HLA-identical sibling marrow transplants.

Paralog: MYO1D

One study found MYO1G (variant rs6958168) to be one of 96 ADHD candidate genes.¹⁴²

1.230. TLR4, Toll Like Receptor 4¶

Other names: HToll; Toll-Like Receptor 4; ARMD10; CD284; TLR-4; Toll Like Receptor 4 Protein; Homolog Of Drosophila Toll; CD284 Antigen; TOLL

The protein TLR4 belongs to the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs generally exist as homodimers (heterodimers have been reported) and are found on immune cells, macrophages, B lymphocytes and mast cells. TLRs are highly conserved from Drosophila to humans and show structural and functional similarities. They recognize pathogen-associated molecular patterns expressed on infectious agents and mediate the production of cytokines necessary for the development of effective immunity. The different TLRs have different expression patterns. In silico studies have shown a particularly strong binding of the surface TLR4 to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). This receptor is also involved in signal transduction triggered by lipopolysaccharide (LPS), which is found in most Gram-negative bacteria. TLR4 cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). TLR4 acts via MYD88, TIRAP and TRAF6 and activates NF-kappa-B, cytokine secretion and inflammatory response. TLR4 is involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). The responses triggered by Ni(2+) require non-conserved histidines and are therefore species-specific. Both M. tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa B expression. TLR4, in complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the first signal is triggered by the binding of oxLDL or amyloid-beta 42 to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers an inflammatory response leading to the NF-kappa-B-dependent production of the cytokines CXCL1, CXCL2 and CCL9 via the MYD88 pathway and the cytokine CCL5 via the TICAM1 pathway, as well as the secretion of IL1B. TLR4 binds electronegative LDL (LDL(-)) and mediates LDL(-)-induced cytokine release. Stimulation of monocytes in vitro with M. tuberculosis PstS1 induces activation of p38 MAPK and ERK1/2 mainly via TLR2, but also partially via the TLR4 receptor. TLR4 is activated by the signaling pathway regulator NMI, which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, thereby promoting the activation of the nuclear factor NF-kappa-B.²⁹⁸
TLR4 is associated with

• age-related macular degeneration 10
• Pyelonephritis
• Differences in LPS sensitivity

Paralog: TLR7

One study found TLR4 (variant rs10121605) as one of 96 ADHD candidate genes.¹⁴²

Stress systems¶

HPA axis¶

1.74. NR3C1, Nuclear Receptor Subfamily 3 Group C Member 1, glucocorticoid receptor (chromosome: 5q31.3)¶

Other names; GR; Glucocorticoid Receptor; GRL; Nuclear Receptor Subfamily 3, Group C, Member 1 (Glucocorticoid Receptor); Nuclear Receptor Subfamily 3 Group C Member 1 Variant HGR-B(54); Nuclear Receptor Subfamily 3 Group C Member 1 Variant HGR-B(77); Nuclear Receptor Subfamily 3 Group C Member 1 Variant HGR-B(93); Nuclear Receptor Subfamily 3, Group C, Member 1; GCRST; GCCR; GCR

OMIM: NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1; NR3C1 (GLUCOCORTICOID RECEPTOR; GCCR; GR GCR; GRL)

The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 causes increased GRβ expression²⁹⁹ and has been associated with ADHD.³⁰⁰ However, the GRβ variant does not bind cortisol, is transcriptionally inactive and is considered a dominant-negative inhibitor of the functional GRα variant.³⁰¹
The GR-9β-stabilizing polymorphism was associated with an increased ACTH and cortisol stress response.³⁰²

The combined inhibitory effect of the GR-9β haplotype and stress exposure may reduce GR activity to pathologically low levels, contributing to ADHD-related behaviors. The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with an increased risk of ADHD. In carriers of this haplotype, stress exposure and ADHD severity correlate more strongly than in non-carriers. This gene-environment interaction was even stronger if the persons with ADHD were also carriers of the homozygous 5-HTTLPR L allele instead of the S allele.³⁰³

In contrast, the Bcll GG haplotype of the GR showed a flattened cortisol stress response in men and a greatly increased cortisol stress response in women (although the test subjects were all using hormonal contraception)³⁰²

1.75. FKBP5, FK506-BINDING PROTEIN 5 (chromosome 6p21.31)¶

OMIM: FK506-BINDING PROTEIN 5; FKBP5

The FKBP5 gene modulates the sensitivity of the glucocorticoid receptor.
In terms of the damage caused by long-term exposure to stress, there is a significant difference between stress in the developmental phase of the brain and in adulthood. Downregulation in adulthood has fewer long-term Consequences. Epigenetic demethylation of the FKBP5 gene, which modulates the sensitivity of glucocorticoid receptors,³⁰⁴ is only mediated by stress during the differentiation and proliferation phase of neurons (i.e. in childhood and adolescence), but no longer in mature neurons (i.e. in adults).³⁰⁵

The FKBP5 gene polymorphisms rs1360780, rs4713916 and rs3800737 cause increased FKBP51 concentrations in the blood and thus an increased cortisol response to psychosocial stress. The re-regulation of the HPA axis is slowed down and remains incomplete for a longer period of time, even after repeated exposure to stress. In contrast, the FKBP5 gene polymorphism Bcl1 shows an anticipatory cortisol response to psychosocial stress.³⁰⁶

1.60. CDH23, CADHERIN 23 (chromosome 10q22.1)¶

The CDH23 gene encodes a member of the cadherin superfamily, which comprises calcium-dependent cell-cell adhesion glycoproteins.
CDH23 is associated with adenomas of the pituitary gland (second increment of the HPA axis). Pituitary adenomas have a prevalence of 14 to 22 %.³⁰⁷

OMIM: CADHERIN 23

The CDH23-SNP rs11594082 Position: 72969259; In intron of CDH23 is a candodata gene for ADHD.¹⁴⁷
p: 1.00E-05

1.254. NAT2, N-acetyltransferase 2¶

Other names: Arylamine N-Acetyltransferase 2; AAC2; N-Acetyltransferase 2 (Arylamine N-Acetyltransferase) 2; N-Acetyltransferase Type 2; Arylamide Acetylase 2; EC 2.3.1.5; NAT-2; PNAT; Polymorphic Arylamine N-Acetyltransferase

The NAT2 protein is an enzyme responsible for the activation and deactivation of arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism, in which human populations are divided into fast, medium and slow acetylator phenotypes. NAT2 is involved in the detoxification of a variety of hydrazine and arylamine drugs. NAT2 catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is capable of bioactivating several known carcinogens.

NAT2 is associated with

• Acetylation, slow
  • NAT2 acetylates among other things³⁰⁸
    • Sulfanilamides
    • Chloramphenicol
    • Glucocorticoids
• multiple chemical sensitivity
• Cancer
• Drug toxicity

Related metabolic pathways:

• Caffeine pathway
• Pharmacokinetics
• Paracetamol-ADME

Paralog: NAT1

One study found NAT2 (variant rs12676224) as one of 96 ADHD candidate genes.¹⁴²
The NAT2 genotypes rr and rs are phenotypically fast eliminators. Drugs that have to be acetylated for excretion (e.g. glucocorticoids) are often ineffective or resistant to therapy in rapid excretors, while slow excretors often have adverse effects.³⁰⁸ Since glucocorticoids are required to restart the HPA axis after a stress response, we consider it conceivable that NAT2-rr and -rs carriers may have a higher risk of HPA axis deactivation problems, which (as can be seen from the ADHD model of SHR) can lead to ADHD-C symptoms.

Oxidative stress¶

1.297. DUSP6, Dual Specificity Phosphatase 6¶

Other names: PYST1; MKP-3; Mitogen-Activated Protein Kinase Phosphatase 3; Dual Specificity Protein Phosphatase PYST1; Dual Specificity Protein Phosphatase 6; MAP Kinase Phosphatase 3; MKP3; Serine/Threonine Specific Protein Phosphatase; EC 3.1.3.16; EC 3.1.3.48; HH19

The protein DUSP6 belongs to the subfamily of protein phosphatases with dual specificity. These phosphatases inactivate their target kinases by dephosphorylation of both phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cell proliferation and differentiation. Different members of the double specificity phosphatase family exhibit different substrate specificities for different MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli.
DUSP6 inactivates MAP kinases, in particular ERK2. DUSP6 is expressed in many tissues, especially in the heart and pancreas. Unlike most other members of this family, DUSP6 is localized in the cytoplasm.
DUSP6 plays an important role in the relief of chronic postoperative pain. DUSP6 is necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery, resulting in the resolution of acute postoperative allodynia. DUSP6 is important for the dephosphorylation of MAPK1/3 in local wound tissue, which further contributes to the resolution of acute pain. DUSP6 promotes cell differentiation by regulating MAPK1/MAPK3 activity and the expression of AP1 transcription factors.³⁰⁹
DUSP6 is associated with

• Hypogonadotropic hypogonadism 19 with or without anosmia
• Normosmic congenital hypogonadotropic hypogonadism

Related signaling pathways:

• MyD88-dependent cascade initiated at the endosome
• Endometrial cancer
• Phosphatase activity
• Phosphoprotein phosphatase activity

Paralog: DUSP7

A study on 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats found that dioscin could help against Parkinson’s disease, as it

• drastically improved the viability of the cells
• reduced the content of reactive oxygen species (ROS)
• improved motor behavior
• Tyrosine hydroxylase (TH) levels increased
• restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats.
  Possible mechanisms of dioscin’s action included an increase in DUSP6 expression levels (by 1.87-fold in cells and 2.56-fold in rats) and regulation of DUSP6, which adjusted the Keap1/Nrf2 signaling pathway. Dioscin protected against oxidative stress via DUSP6 signaling.³¹⁰

The MAPK phosphatase MKP3/DUSP6 is an inhibitor of mitogen-activated protein kinase (MAPK) and prevents the depolarization-dependent release of dopamine in rat PC12 cells³¹¹

DUSP6 was identified as an ADHD candidate gene in a large GWAS.¹⁷⁰

Further consequences of stress¶

1.108. NCL, Nucleolin¶

Other names: Nsr1, C23, Protein C23

NCL is the most important eukaryotic nucleolar phosphoprotein and is involved in the synthesis and maturation of ribosomes. It is mainly located in dense fibrillar regions of the nucleolus. NCL induces chromatin decondensation by binding to histone H1. NCL appears to play a role in pre-rRNA transcription and ribosome assembly and to be involved in the process of transcription elongation. NCL is involved in an astonishing number of molecular processes NCL interacts with many types of molecules and regulates many facets of DNA and RNA metabolism.

Nucleolin (and ELAVL1) act independently with MBII-52 snoRNA by co-immunoprecipitation.
snoRNAs are small nucleolar RNAs and are among the most abundant non-coding RNA species in all organisms. They are required for the maturation of the pre-ribosomal RNA (pre-rRNA) in the nucleolus. In contrast to the known snoRNAs, brain-specific snoRNAs lack complementarity to pre-rRNAs or pre-snRNAs, which is why they are referred to as “orphan snoRNAs”. In contrast to canonical snoRNAs, which target snRNAs or rRNAs, the orphan snoRNA MBII-52 has an 18-nucleotide complementarity to the pre-mRNA of the serotonin 2C receptor and thus reduces its mRNA expression.³¹²

NCL³¹³

• is a histone chaperone and a chromatin remodeler that is involved in DNA repair, replication and recombination.
• is involved in the transcription and maturation of ribosomal RNA as well as in the assembly and transport of ribosomes.
• is involved in the transcription, splicing, stability, transport and translation of many mRNAs.
• in the cytosol contributes to the anchoring of microtubules to the centrosomes in interphase cells and to microtubule polymerization.
• regulates the assembly and interaction of Ras proteins and MAPK signal transduction at the plasma membrane.
• acts on the cell surface as a co-receptor for cytokines, growth factors and matrix proteins
• is subsequently involved in numerous pathologies.
• involved in³¹⁴
  • Cell proliferation
  • Angiogenesis
  • Apoptosis regulation
  • Stress reaction
  • microRNA processing

NCL is associated with

• Ependymoma in childhood
• Spinal muscular atrophy
• Cancer
• Viral diseases
• neurodegenerative diseases

Stress conditions such as heat shock, γ-irradiation and camptothecin administrationcan cause a dramatic redistribution of NCL from the nucleolus to the nucleoplasm in a p53-dependent manner. This can transiently impair DNA replication and repair. The interaction between stress-activated nucleoplasmic p53 and NCL prevents p53 from being imported into the nucleolus, leading to its accumulation in the nuclear matrix. After stress stimulation, NCL can undergo specific post-translational modification, such as serine phosphorylation by casein kinase II, which promotes the interaction of NCL with RPA (replication protein A), and accumulation occurs in the nucleoplasm because the nucleoplasm contains a large amount of RPA. This redistribution is associated with increased formation of the NCLRPA complex, which further inhibits initiation and elongation during DNA replication.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷
Another study found NCL (variant rs16828074) to be the most likely of 96 candidate genes.¹⁴²

Broadly effective mechanisms¶

Transcription¶

1.95. RERE¶

The RERE protein is crucial for normal development before birth. A lack of RERE function likely alters the activity of many genes involved in pre-birth development. These changes prevent the normal development of tissues in the brain, eyes, heart and other organs. The RERE protein interacts with other proteins, called transcription factors, which control the activity (transcription) of certain genes. The RERE protein helps these transcription factors turn on (activate) and turn off (repress) a number of genes that are important for early development, ensuring that the genes are activated (expressed) at the right time and in the right place for proper tissue formation. Research suggests that the RERE protein plays a role in the development of the brain, eyes, inner ear, heart and kidneys.³¹⁵

One study found RERE to be one of the 51 most likely candidate genes for ADHD.⁷

1.45. HES1; HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 1 (chromosome 3q29)¶

The HES1 protein belongs to the bHLH (basic helix-loop-helix) family of transcription factors. It is a transcriptional repressor of genes that require a bHLH protein for their transcription. As a member of the bHLH family, it is a transcriptional repressor that influences cell proliferation and differentiation during embryogenesis. HES1 regulates its own expression via a negative feedback loop and oscillates with a periodicity of about 2 hours.

OMIM: HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 1; HES1

The HES1 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.016.³

1.86. FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1¶

Not to be confused with FEZ1.

The protein FEZF1 is a transcriptional repressor. In mice, FEZF1 is expressed in the forebrain during the early development of the embryo.
FEZF1 represses the transcription factor HES5, which helps to control the differentiation of neural stem cells. FEZF1 helps to divide the caudal forebrain into the three different parts prethalamus, thalamus and pretectum during development: FEZF1-KO mice have no prethalamus and a smaller thalamus.
A loss-of-function mutation in FEZF1 causes Kallmann syndrome.
As axons develop and migrate in the early embryo, FEZF1 enables olfactory neuron axons to connect to the central nervous system in the mouse model. During neuronal development, GnRH neurons migrate through one of these olfactory axon pathways, and the loss of function of FEZF1 therefore leads to the loss of GnRH neurons in the brain, the hallmark of Kallmann syndrome.³¹⁶

OMIM: FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1

FEZF1 is a candidate gene for ADHD.³¹⁷

1.143. ZNF763, Zinc Finger Protein 763¶

Other NAmen: ZNF440L, Zinc Finger Protein 440 Like, DNA-Binding Protein, ZNF

The protein ZNF763 is thought to be involved in transcriptional regulation through RNA polymerase II. ZNF763 appears to have a DNA-binding transcription factor activity and a sequence-specific DNA-binding activity in the cis-regulatory region of RNA polymerase II. ZNF763 is presumably localized in the nucleus.³¹⁸

ZNF763 is a candidate gene for ADHD.²¹⁷

1.134. ZNF615, Zinc Finger Protein 615¶

Other name: FLJ33710

The protein ZNF615 enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA-binding activity. ZNF615 is probably involved in the regulation of transcription by RNA polymerase II. ZNF615 is probably active in the nucleus.³¹⁹

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.139. POLR1H, RNA polymerase I subunit H¶

Other names: Tctex-6, HTEX-6, HZR14, RPA12, A12, ZNRD1, DNA-Directed RNA Polymerase I Subunit RPA12, DNA-Directed RNA Polymerase I Subunit H, Zinc Ribbon Domain Containing 1, RNA Polymerase I Small Specific Subunit Rpa12, Transcription-Associated Zinc Ribbon Protein, Zinc Ribbon Domain-Containing Protein 1, TCTEX6, HTEX6, Rpa12, TEX6, ZR14, ZNRD1, ZINC RIBBON DOMAIN-CONTAINING PROTEIN 1, MOUSE, HOMOLOG OF; A12.2

The POLR1H protein is a DNA-controlled RNA polymerase I subunit. It may play a role in the regulation of cell proliferation. POLR1H catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. POLR1H is a component of RNA polymerase I.³²⁰ RNA polymerase (Pol) I produces ribosomal (r)RNA, an essential component of the cellular protein synthesis machinery that drives cell growth and underlies many fundamental cellular processes. Transcription by Pol I is subject to a series of intricate control mechanisms that influence rRNA production. Pol I-specific transcription factors direct Pol I to the rDNA promoter and contribute to multiple rounds of transcription initiation, promoter escape, elongation and termination.³²¹
POLR1H is associated with

• Progression of cancer
• HIV
• Asthma
• Nasal polyps
• Aspirin intolerance
• Plantar warts

OMIM: ZNRD1, ZINC RIBBON DOMAIN-CONTAINING PROTEIN 1

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

Receptor activity¶

1.41. ARRB2, arrestin beta 2 gene (chromosome 17p13.2)¶

The protein β-arrestin (also β-arrestin 1, arrestin 2) regulates the activity of G protein-coupled receptors (GPCR). It causes

• reduced GPCR activation
• Endocytosis of the GPCR
• Connection of GPCR signaling pathway with Src signaling pathway
• Connection between the ERK signaling pathway and the Akt signaling pathway.

OMIM: Arrestin beta 2 gene, ARRB2

The ARRB2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.004.³

Neurotransmitter storage¶

1.49. SYP, SYNAPTOPHYSIN (chromosome Xp11.23)¶

Synaptophysin is found in synaptic vesicles of neurons in the brain, spinal cord and retina as well as in similar vesicles in the adrenal medulla and motor end plate.
Little is known about the function of synaptophysin. It appears to form a channel in the membrane of nerve cells, which enables the uptake of neurotransmitters from the cytosol into the synaptic vesicles.

OMIM: SYNAPTOPHYSIN; SYP

The SYP gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.045.³

Purine metabolism¶

1.115. NT5C2, 5’-nucleotidase, Cytosolic II¶

Other names: CN-II, PNT5, SPG65, NT5B, GMP, Spastic Paraplegia 45 (Autosomal Recessive), Cytosolic Nucleoside Phosphotransferase 5’N, 5’-Nucleotidase (Purine), Cytosolic Type B, Cytosolic IMP/GMP-Specific 5’-Nucleotidase, Cytosolic Purine 5’-Nucleotidase

The protein NT5C2 is a hydrolase and a cytosolic 5’-nucleotidase with broad specificity. NT5C2 plays an important role in cellular purine metabolism. NT5C2 mainly acts on inosine 5’-monophosphate and other purine nucleotides. NT5C2 catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5’-monophosphates. NT5C2 has a phosphotransferase activity by which it can transfer a phosphate from a donor nucleoside monophosphate to an acceptor nucleoside, preferably inosine, deoxyinosine and guanosine.³²²

NT5C2 is associated with

• Chemotherapy resistance in relapsed acute lymphoblastic T-cell leukemia.
• Spastic paraplegia 45, autosomal recessive
• Paraplegia

One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

Adhesion¶

1.288. PCDH7, protocadherin 7¶

Other names: BH-Pcdh; PPP1R120; Protein Phosphatase 1, Regulatory Subunit 120; BH-Protocadherin (Brain-Heart); Brain-Heart Protocadherin; Protocadherin-7; BHPCDH

PCDH7 belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The PCDH7 protein is an integral membrane protein that appears to play a role in cell-cell recognition and adhesion and has an extracellular domain containing 7 cadherin repeats.³²³
The expression of PCDH7 increases during cocaine withdrawal.³²⁴
PCDH7 is associated with

• Astigmatism
• Epilepsy, myoclonic juvenility

Related signaling pathways:

• Response to elevated platelet cytosolic Ca2+
• RHOC GTPase cycle
• Calcium ion binding

Paralog: PCDH1

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁷⁰

1.53. SPATA13, SPERMATOGENESIS-ASSOCIATED PROTEIN 13 (chromosome 13q12.12)¶

Other names: FLJ31208; Spermatogenesis Associated 13, ARHGEF29; ASEF2; APC-Stimulated Guanine Nucleotide Exchange Factor

The protein SPATA13 enables guanyl nucleotide exchange factor activity for the GTPases RHOA, RAC1 and CDC42 and identical protein binding activity. SPATA13 is involved in cell migration, formation of plasma membrane-bound cell extensions, regulation of cell migration, and adhesion assembly and disassembly through a mechanism dependent on RAC1, PI3K, RHOA and AKT1. SPATA13 increases both RAC1 and CDC42 activity, but decreases the amount of active RHOA. SPATA13 is required for the upregulation of MMP9 via the JNK signaling pathway in colorectal tumor cells. SPATA13 is involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression. SPATA13 is found in several cellular components, including filopodium, lamellipodium and curling membrane.³²⁵
SPATA13 is associated with

• Optical atrophy 3, autosomal dominant
• Dravet syndrome

OMIM: SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13

• SNP: rs17079773 Position: 23496384; In intron of SPATA13 ¹⁴⁷
  Associated with inattention
  p: 4.71E-06

1.58. ITGAE, integrin subunit alpha E (chromosome 17p3.2)¶

Other names: HUMINAE; CD103; Integrin, Alpha E (Antigen CD103, Human Mucosal Lymphocyte Antigen 1; Alpha Polypeptide); Human Mucosal Lymphocyte Antigen 1, Alpha Polypeptide; Mucosal Lymphocyte 1 Antigen; Integrin Alpha-IEL; Integrin Alpha-E; HML-1 Antigen; Antigen CD103, Human Mucosal Lymphocyte Antigen 1; Alpha Polypeptide; Antigen CD103; CD103 Antigen; CD103

Integrins are heterodimeric integral membrane proteins and consist of an alpha chain and a beta chain. As transmembrane proteins, they cross the cell membrane, in which they are firmly anchored. They play an important role in cell signal transduction. They connect individual cells with each other and cells with the extracellular matrix (adhesion). Integrins are therefore also called adhesion molecules.
ITGAE is a receptor for E-cadherin. It binds integrin beta 7 (β7- ITGB7) to form the complete heterodimeric integrin molecule αEβ7. ITGAE mediates adhesion of intra-epithelial T lymphocytes to epithelial cell monolayers. ITGAE is an I-domain-containing alpha integrin that undergoes post-translational cleavage in the extracellular domain to form disulfide-linked heavy and light chains. In combination with the beta-7 integrin, this protein forms the E-cadherin-binding integrin known as human mucosal lymphocyte-1 antigen. ITGAE is preferentially expressed in human intestinal intraepithelial lymphocytes (IEL) and, in addition to its role in adhesion, may also serve as an accessory molecule for IEL activation.³²⁶
ITGAE is associated with

• Enteropathy-associated T-cell lymphoma
• Mycosis Fungoides

Related signal paths:

• Autophagy signaling pathway
• Dendritic Cells Developmental Lineage Pathway

Paralog: ITGA11.

OMIM: INTEGRIN, ALPHA-E

• SNP: rs220470 Position: 3611724; In intron of ITGAE¹⁴⁷
  P: 1.34E-07
  One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

1.59. ITGA11, integrin subunit alpha 11 (chromosome 15q23)¶

Other names: HsT18964; Integrin Alpha-11; Integrin, Alpha 11

Integrins are heterodimeric integral membrane proteins and consist of an alpha chain and a beta chain. As transmembrane proteins, they cross the cell membrane, in which they are firmly anchored. They play an important role in cell signal transduction. They connect individual cells with each other and cells with the extracellular matrix (adhesion). Integrins are therefore also called adhesion molecules.
The protein ITGA11 is an alpha integrin and contains an I-domain. ITGA11 is expressed in muscle tissue and dimerizes in vitro with beta-1 integrin, whereby it appears to bind collagen. Integrin alpha-11/beta-1 is a collagen receptor. Therefore, ITGA11 may be involved in the binding of muscle tissue to the extracellular matrix.³²⁷
ITGA11 is associated with

• Oligodendroglioma of the brain
• Myasthenic syndrome, congenital, 19

Related signal paths:

• Autophagy signaling pathway
• PI3K-Akt signal path
• Collagen binding
• Collagen receptor activity

Paralog: ITGA10.

OMIM: INTEGRIN, ALPHA-11

• Rs7164335 66502086 In intron of ITGA11¹⁴⁷
  p: 1.30E-07
  One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁷

Cerebral damage¶

1.287. SPAG16, Sperm Associated Antigen 16¶

Other names: PF20; WDR29; Sperm-Associated Antigen 16 Protein; Pf20 Protein Homolog; DKFZp666P1710; FLJ22724; Sperm-Associated WD Repeat Protein; WD Repeat Domain 29

SPAG16 is required for the function of the sperm flagella. SPAG16 encodes two major proteins associated with the axoneme of the sperm tail and the nucleus of the postmeiotic germ cells, respectively. The axoneme is a microtubular backbone composed of cilia and flagella organized by the basal body and surrounded by a plasma membrane. SPAG16 plays a role in the formation of motile cilia. SPAG16 is required for sperm flagellar function and may contribute to the recruitment of STK36 to the cilium or apical surface of the cell to initiate subsequent steps in the assembly of the central pair apparatus of motile cilia.³²⁸
SPAG16 is associated with

• Pulmonary subvalvular stenosis (narrowing of the outflow tract of the right ventricle to the pulmonary artery)
• Brain Small Vessel Disease 2
  • Cerebral disease of the small vessels
  • Can lead to cognitive deficits in the areas of attention and executive function³²⁹

Related signaling pathway: protein kinase binding.

SPAG16 was identified as an ADHD candidate gene in a large GWAS.¹⁷⁰