Genome-wide association studies in ADHD.
- Authors
- Franke, Barbara; Neale, Benjamin M; Faraone, Stephen V
- Year
- 2009
- Journal
- Human genetics
- PMID
- 19384554
- DOI
- 10.1007/s00439-009-0663-4
- PMCID
- PMC3774416
Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent-child trio's collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the 'classic' ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence-as yet-points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of 'new' neurotransmission and cell-cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important.
Simplified schematic representation of the endophenotype concept in psychiatric genetics. Many genes (depicted in an oversimplified way as gene A to I) are involved in causing a disease symptom and the categorical disease phenotype. A reduced number of genes is involved in disease related endophenotypes, like βFunction of a brain unitβ (Level 1), as assessed through performance on neuropsychological tests; even less genes play a role if an endophenotype at levels 2 or 3 is used for genetic association studies. On level 2, endophenotypes measured through (structural and functional) neuroimaging are shown, on level 3 cellular behavior, assessed through e.g. assays measuring migration, apoptosis or cell division rates are shown
| Name | Type |
|---|---|
| 50 K GWAS local | cohort |
| 50K GWAS local | cohort |
| ADAMTS2 local | gene |
| addiction | phenotype |
| addiction phenotypes | phenotype |
| addiction-related disorders local | phenotype |
| ADHD | phenotype |
| ADHD-affected adults local | cohort |
| ADHD GWAS | cohort |
| ADHD inattentive symptoms | phenotype |
| ADHD overall symptoms local | phenotype |
| ADHD phenotype local | phenotype |
| ADHD symptoms | phenotype |
| adolescents | cohort |
| adoptive parents | cohort |
| Adra1a | gene |
| ADRB2 | gene |
| adult ADHD patients local | cohort |
| adults | cohort |
| affective disorders | phenotype |
| Affymetrix GeneChip Human Mapping 500K local | drug |
| age of onset of ADHD symptoms local | phenotype |
| Age of onset of ADHD symptoms local | phenotype |
| aggression | phenotype |
| AK094352 local | gene |
| AK128216 local | gene |
| AK309325 local | gene |
| alcohol and drug abuse and dependence local | phenotype |
| alcohol dependence | phenotype |
| Alcohol Use | phenotype |
| Allen-Brady et al. 2008 local | cohort |
| all symptoms local | phenotype |
| Alzheimer's disease | phenotype |
| Alzheimerβs disease | phenotype |
| amygdala | anatomy |
| amyotrophic lateral sclerosis | phenotype |
| anorexia nervosa | phenotype |
| ARHGAP22 local | gene |
| ASTN local | gene |
| ASTN2 | gene |
| ATP2C2 | gene |
| AURKC local | gene |
| autism | phenotype |
| autism spectrum disorder | phenotype |
| autoaggressive behavior local | phenotype |
| autosomal SNP local | variant |
| autosomal SNPs | cohort |
| BC032407 local | gene |
| BCAS1 local | gene |
| Bdnf | gene |
| biological parents of hyperactive children local | cohort |
| bipolar disorder | phenotype |
| BMP | drug |
| brain | anatomy |
| brain activity | phenotype |
| brain disorder local | phenotype |
| brain ependymal cells local | anatomy |
| brain structure | anatomy |
| Brookes et al. 2006 local | cohort |
| C10orf79 local | gene |
| C3orf21 local | gene |
| C9orf98 local | gene |
| Ca2+ | drug |
| cadherin local | drug |
| CAMK2G | gene |
| cAMP | drug |
| cannabis use | phenotype |
| cardiovascular disease | phenotype |
| cases | cohort |
| categorical ADHD phenotype local | phenotype |
| Caucasian caseβparent-trios local | cohort |
| caudate nucleus | anatomy |
| CDH13 | gene |
| CDH23 local | gene |
| cerebellum | anatomy |
| children | cohort |
| Chrna4 | gene |
| cluster B personality disorder | phenotype |
| CLYB local | gene |
| Cnr1 | gene |
| CNV | variant |
| coding variant in KIF6 local | variant |
| common variants | cohort |
| COMT | gene |
| conduct disorder | phenotype |
| Conners ADHD Rating Scale local | phenotype |
| control | cohort |
| controls | cohort |
| controls unscreened for psychiatric disorders local | cohort |
| copy number variant | variant |
| CREB5 | gene |
| CRYGC local | gene |
| CSMD1 | gene |
| CSMD2 | gene |
| CTNNA2 | gene |
| DA259379 local | gene |
| DBH | gene |
| DCLK1 | gene |
| DDC | gene |
| deafness | phenotype |
| depression | phenotype |
| developmental speech and language disorder local | phenotype |
| developmental speech and language disorders local | phenotype |
| diacylglycerol | drug |
| disease | phenotype |
| DMRT2 local | gene |
| DNA methylation | drug |
| DNM1 | gene |
| DPP10 | gene |
| Dpp6 | gene |
| DRD2 | gene |
| drug abuse and dependence local | phenotype |
| drug dependence | phenotype |
| earlier onset local | phenotype |
| Earlier onset local | phenotype |
| early age of onset of ADHD symptoms local | phenotype |
| EGF receptor local | drug |
| endophenotype | phenotype |
| environmental factors | drug |
| epilepsy | phenotype |
| EREG | gene |
| ESRRB local | gene |
| extracellular matrix | drug |
| FAM19A3 local | gene |
| family-based association study local | cohort |
| FAT3 local | gene |
| FBAT-PC all symptoms local | phenotype |
| fetal brain | anatomy |
| FHIT | cohort |
| first-degree adoptive relatives of probands with ADHD local | cohort |
| first-degree biological relatives of non-adopted ADHD probands local | cohort |
| Foxp1 | gene |
| Foxp2 | gene |
| Fullerton et al. 2003 linkage study local | cohort |
| GAIN | cohort |
| GAIN dataset | cohort |
| GAIN/IMAGE local | cohort |
| GAIN/IMAGE ADHD dataset local | cohort |
| GAIN/IMAGE dataset local | cohort |
| GAIN/IMAGE GWAS studies local | cohort |
| GAIN/IMAGE participants local | cohort |
| GAIN/IMAGE sample local | cohort |
| geneβenvironment interaction local | drug |
| geneβgene interaction local | drug |
| genetic disorders | phenotype |
| German ADHD cohort local | cohort |
| GFOD1 | gene |
| glutamate | drug |
| GPC6 | gene |
| GRB10 | gene |
| GRIK1 | gene |
| GWAS sample used by Lesch et al. (2008) local | cohort |
| HapMap | cohort |
| HAS3 local | gene |
| heparan sulfate proteoglycans | drug |
| heteroaggressive behavior local | phenotype |
| hippocampus | anatomy |
| HTR1E local | gene |
| Htr2a | gene |
| human brain | anatomy |
| hyaluronic acid local | drug |
| hyperactive-impulsive symptom local | phenotype |
| hyperactive-impulsive symptoms local | phenotype |
| hyperactiveβimpulsive symptoms local | phenotype |
| hyperactivity | phenotype |
| hypothalamus | anatomy |
| IL16 | gene |
| IMAGE local | cohort |
| impulsive and aggressive behavior local | phenotype |
| impulsivity | phenotype |
| inattentive symptom local | phenotype |
| Inattentive symptom count local | phenotype |
| integrin | drug |
| Integrins local | gene |
| interleukin 16 local | drug |
| International Multicentre ADHD Genetics (IMAGE) study local | cohort |
| Irmansyah et al. 2008 local | cohort |
| ITGA11 local | gene |
| ITGAE local | gene |
| ITPR2 local | gene |
| KALRN local | gene |
| Kcnc1 | gene |
| KCNIP1 | gene |
| KCNIP4 local | gene |
| KIAA0574 local | gene |
| KIAA1486 local | gene |
| KIF6 local | gene |
| KIF6 coding variant local | variant |
| Lasky-Su et al. 2008b local | cohort |
| Lasky-Su et al. 2008b GWAS local | cohort |
| Lasky-Su et al. 2008 GWAS local | cohort |
| Lasky-Su study local | cohort |
| later onset local | phenotype |
| Later onset local | phenotype |
| Lesch et al. 2008 ADHD study local | cohort |
| Lesch et al. 2008 study local | cohort |
| Lewis et al. 2003 local | cohort |
| Lewis et al. 2003 meta-analysis local | cohort |
| Lewis et al. 2003 schizophrenia meta-analysis local | cohort |
| Li et al. 2008 local | cohort |
| linkage paper dataset local | cohort |
| lipid-related disorders local | phenotype |
| low-frequency variant | variant |
| low IQ | phenotype |
| LPL | gene |
| major depressive disorder | phenotype |
| MAN2A2 local | gene |
| MAP1B | gene |
| MAP3K5 local | gene |
| MAP3K7 local | gene |
| Marshall et al. 2008 local | cohort |
| maternal criticism local | phenotype |
| Maternal criticism local | phenotype |
| maternal expressed emotion local | phenotype |
| maternal warmth | phenotype |
| MBOAT1 local | gene |
| medulla | anatomy |
| MEIS2 local | gene |
| memory | phenotype |
| metamphetamine local | drug |
| Metamphetamine local | drug |
| methamphetamine | drug |
| methamphetamine dependence | phenotype |
| MGC48628 local | gene |
| MMP24 local | gene |
| Mn2+ | drug |
| Mn2+ ions local | drug |
| MOBP | gene |
| mother's criticism local | drug |
| mother's warmth local | drug |
| motherβs warmth local | phenotype |
| MTA3 local | gene |
| Myt1l | gene |
| NAD+ | drug |
| NAP1L5 | gene |
| NAPRT1 local | gene |
| NAV2 local | gene |
| Neale et al. 2008a local | cohort |
| Neale et al. 2008a GWAS local | cohort |
| Neale et al. 2008 GWAS local | cohort |
| neurodegenerative diseases | phenotype |
| Neuroimaging | phenotype |
| neuropsychological deficits | phenotype |
| neuroticism | phenotype |
| niacin local | drug |
| nicotine dependence | phenotype |
| NIMH | cohort |
| nitric oxide | drug |
| NM23-1 local | gene |
| NM23-2 local | gene |
| NMDA receptor | drug |
| NME1 local | gene |
| NME2 local | gene |
| NO | drug |
| non-syndromal hearing loss local | phenotype |
| Nos1 | gene |
| NOS1 SNP local | variant |
| NT5DC3 local | gene |
| NUCB1 local | gene |
| NUCB2 local | gene |
| PACS local | phenotype |
| palmitoyl local | drug |
| Parkinsonβs disease | phenotype |
| PCDP1 local | gene |
| PER1 | gene |
| Perlegen microarray local | drug |
| persistent ADHD local | phenotype |
| Persistent ADHD local | phenotype |
| PEX7 local | gene |
| PIWIL4 local | gene |
| potassium channel local | drug |
| potassium channel subunits local | drug |
| PPM1F local | gene |
| prefrontal cortex | anatomy |
| presenilin | gene |
| psychiatric disorders | phenotype |
| Psychiatric Genomics Consortium | cohort |
| PTPN14 local | gene |
| PTPRN2 local | gene |
| quantitative ADHD-related phenotypes local | phenotype |
| quantitative ADHD symptom measures local | phenotype |
| RAB27B local | gene |
| Rab38 | gene |
| rare variant | cohort |
| REEP5 local | gene |
| retinoic acid | drug |
| RORA | gene |
| rs10039254 local | variant |
| rs10049246 local | variant |
| rs1018040 local | variant |
| rs10227331 local | variant |
| rs10421632 local | variant |
| rs10514604 local | variant |
| rs10767942 local | variant |
| rs10786284 local | variant |
| rs10865184 local | variant |
| rs10895959 local | variant |
| rs10983238 local | variant |
| rs11221064 local | variant |
| rs11243897 local | variant |
| rs11590090 local | variant |
| rs115940825 local | variant |
| rs1161453 local | variant |
| rs1161457 local | variant |
| rs1161463 local | variant |
| rs116464117 local | variant |
| rs11646411797 local | variant |
| rs11719664 local | variant |
| rs11752175 local | variant |
| rs11786458 local | variant |
| rs11790994 local | variant |
| rs1202199 local | variant |
| rs12453316 local | variant |
| rs124533166 local | variant |
| rs125055021 local | variant |
| rs12679254 local | variant |
| rs127727370 local | variant |
| rs130575 local | variant |
| rs1325154 local | variant |
| rs13330107 local | variant |
| rs13353224 local | variant |
| rs1335515 local | variant |
| rs13395022 local | variant |
| rs133950225 local | variant |
| rs1350666 local | variant |
| rs14273240 local | variant |
| rs1471225 local | variant |
| rs1514928 local | variant |
| rs1517484 local | variant |
| rs15395490 local | variant |
| rs15416650 local | variant |
| rs1555322 local | variant |
| rs1692852 local | variant |
| rs17079773 local | variant |
| rs17281813 local | variant |
| rs17367118 local | variant |
| rs17641078 local | variant |
| rs17651978 local | variant |
| rs17658378 local | variant |
| rs17722514 local | variant |
| rs177542821 local | variant |
| rs1792040 local | variant |
| rs1918172 local | variant |
| rs2014572 local | variant |
| rs2199161 local | variant |
| rs21991611 local | variant |
| rs22047028 local | variant |
| rs2212361 local | variant |
| rs22373496 local | variant |
| rs2241685 local | variant |
| rs22420734 local | variant |
| rs2281597 local | variant |
| rs2290416 local | variant |
| rs2295426 local | variant |
| rs2311120 local | variant |
| rs23111200 local | variant |
| rs2360997 local | variant |
| rs2502731 local | variant |
| rs2587695 local | variant |
| rs260461 local | variant |
| rs2677744 local | variant |
| rs26787870 local | variant |
| rs272000 local | variant |
| rs2769967 local | variant |
| rs2825388 local | variant |
| rs2827093 local | variant |
| rs284264370 local | variant |
| rs3776816 local | variant |
| rs37823091 local | variant |
| rs3799977804 local | variant |
| rs3892715 local | variant |
| rs38932157 local | variant |
| rs4120502 local | variant |
| rs412050235 local | variant |
| rs4128767 local | variant |
| rs41441749 local | variant |
| rs4147141 local | variant |
| rs42411120 local | variant |
| rs4650135 local | variant |
| rs469727557 local | variant |
| rs4714261 local | variant |
| rs478597 local | variant |
| rs4810685 local | variant |
| rs4875598 local | variant |
| rs4964805 local | variant |
| rs49648053 local | variant |
| rs515910244 local | variant |
| rs522958 local | variant |
| rs552655 local | variant |
| rs6565113 local | variant |
| rs65704260 local | variant |
| rs66577490 local | variant |
| rs6719977 local | variant |
| rs6791644 local | variant |
| rs6808138 local | variant |
| rs69198570 local | variant |
| rs6968385 local | variant |
| rs708188 local | variant |
| rs7126782 local | variant |
| rs71643355 local | variant |
| rs7172689 local | variant |
| rs7175404 local | variant |
| rs71872230 local | variant |
| rs7495052 local | variant |
| rs7577925 local | variant |
| rs76576081 local | variant |
| rs7816032 local | variant |
| rs7992643 local | variant |
| rs79952155 local | variant |
| rs8041675 local | variant |
| rs8047014 local | variant |
| rs806276 local | variant |
| rs864643 local | variant |
| rs874426 local | variant |
| rs8764771 local | variant |
| rs9227811 local | variant |
| rs930421 local | variant |
| rs9389835 local | variant |
| rs9451437 local | variant |
| rs94844480 local | variant |
| rs96086171 local | variant |
| rs9646471 local | variant |
| rs9676447 local | variant |
| rs9687070 local | variant |
| rs9845475 local | variant |
| s363512 local | variant |
| schizophrenia | phenotype |
| SDK2 local | gene |
| sex | phenotype |
| single nucleotide polymorphism | variant |
| SLC46A3 local | gene |
| SLC6A1 | gene |
| SLC6A2 | gene |
| SLC6A3 | gene |
| SLC6A3 haplotype local | variant |
| SLC9A9 | gene |
| SLCO3A1 | gene |
| smoking | phenotype |
| SNAI1 | gene |
| Snap25 | gene |
| SNP | cohort |
| Sonuga-Barke et al. 2008 local | cohort |
| SPATA13 local | gene |
| spinal cord | anatomy |
| SPOCK3 local | gene |
| statins | drug |
| stroke | phenotype |
| substance abuse | phenotype |
| substance use | phenotype |
| substantia nigra | anatomy |
| SULF2 local | gene |
| Sullivan et al. 2008 local | cohort |
| Sullivan et al. 2008 GWAS local | cohort |
| SUPT3H local | gene |
| SYT1 local | gene |
| SYT16 local | gene |
| Szatmari et al. 2007b local | cohort |
| TAFA proteins local | drug |
| TFEB local | gene |
| TGF-Ξ² | drug |
| thalamus | anatomy |
| TLL1 | gene |
| TLL2 local | gene |
| TMCO7 local | gene |
| total ADHD symptom count local | phenotype |
| total ADHD symptoms local | phenotype |
| total cholesterol | phenotype |
| total number of symptoms local | phenotype |
| TPH2 | gene |
| trait | phenotype |
| triglycerides | phenotype |
| TRIM71 local | gene |
| trios cohort local | cohort |
| TRPS1 | gene |
| TRUB1 local | gene |
| type 2 diabetes | phenotype |
| Unc5b | gene |
| vasopressin | drug |
| Welcome Trust Case Control Consortium local | cohort |
| Wellcome Trust case control consortium | cohort |
| Wellcome Trust Case Control Consortium 2007 local | cohort |
| Wellcome Trust Case Control Consortium 2007 GWAS local | cohort |
| WRNIP1 local | gene |
| Zhou et al. 2008c local | cohort |
| Zhou et al. 2008 meta-analysis local | cohort |
| ZNF354C local | gene |
| ZNF385D local | gene |
| ZNF423 local | gene |
| ZNF544 local | gene |
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In this knowledge base
External
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