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1476-468745972462009May28NatureNatureCommon genetic variants on 5p14.1 associate with autism spectrum disorders.528533528-3310.1038/nature07999Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.WangKaiKCenter for Applied Genomics, Children's Hospital of Philadelphia, Pennsylvania 19104, USA.ZhangHaitaoHMaDeqiongDBucanMajaMGlessnerJoseph TJTAbrahamsBrett SBSSalyakinaDariaDImielinskiMarcinMBradfieldJonathan PJPSleimanPatrick M APMKimCecilia ECEHouCuipingCFrackeltonEdwardEChiavacciRosettaRTakahashiNagahideNSakuraiTakeshiTRappaportEricELajonchereClara MCMMunsonJeffreyJEstesAnnetteAKorvatskaOlenaOPivenJosephJSonnenblickLisa ILIAlvarez RetuertoAna IAIHermanEdward IEIDongHongmeiHHutmanTedTSigmanMarianMOzonoffSallySKlinAmiAOwleyThomasTSweeneyJohn AJABruneCamille WCWCantorRita MRMBernierRaphaelRGilbertJohn RJRCuccaroMichael LMLMcMahonWilliam MWMMillerJudithJStateMatthew WMWWassinkThomas HTHCoonHilaryHLevySusan ESESchultzRobert TRTNurnbergerJohn IJIHainesJonathan LJLSutcliffeJames SJSCookEdwin HEHMinshewNancy JNJBuxbaumJoseph DJDDawsonGeraldineGGrantStruan F ASFGeschwindDaniel HDHPericak-VanceMargaret AMASchellenbergGerard DGDHakonarsonHakonHengMH0666730MHNIMH NIH HHSUnited StatesNS049261NSNINDS NIH HHSUnited States1U24MH081810MHNIMH NIH HHSUnited StatesN01-HD-4-3368HDNICHD NIH HHSUnited StatesR01 NS036768NSNINDS NIH HHSUnited StatesP50 HD055748HDNICHD NIH HHSUnited StatesP50 HD055784HDNICHD NIH HHSUnited StatesR01 MH064547MHNIMH NIH HHSUnited StatesUL1-RR024134-03RRNCRR NIH HHSUnited StatesMH69359MHNIMH NIH HHSUnited StatesU54 MH066673MHNIMH NIH HHSUnited StatesU24 MH081810MHNIMH NIH HHSUnited StatesP50 HD055782HDNICHD NIH HHSUnited StatesMH64547MHNIMH NIH HHSUnited StatesM01-RR00064RRNCRR NIH HHSUnited StatesR01 NS049261NSNINDS NIH HHSUnited StatesP01 NS026630NSNINDS NIH HHSUnited StatesN01-HD-4-3383HDNICHD NIH HHSUnited StatesMH080647MHNIMH NIH HHSUnited StatesMH061009MHNIMH NIH HHSUnited StatesR01 MH061009MHNIMH NIH HHSUnited StatesMH081754MHNIMH NIH HHSUnited StatesNS26630NSNINDS NIH HHSUnited StatesR01 MH068398MHNIMH NIH HHSUnited StatesP50 HD055751HDNICHD NIH HHSUnited StatesMRC_Medical Research CouncilUnited KingdomR01 MH080647MHNIMH NIH HHSUnited StatesHD055784HDNICHD NIH HHSUnited StatesR01 MH081754MHNIMH NIH HHSUnited StatesNS36768NSNINDS NIH HHSUnited StatesR01 MH069359MHNIMH NIH HHSUnited StatesHD055782-01HDNICHD NIH HHSUnited StatesM01 RR000064RRNCRR NIH HHSUnited StatesUL1 RR024134RRNCRR NIH HHSUnited StatesHD055751HDNICHD NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.20090428
EnglandNature04104620028-08360CDH10 protein, human0CDH9 protein, human0Cadherins0Cell Adhesion Molecules, Neuronal0Genetic MarkersIMAutistic DisordergeneticsBrainmetabolismCadherinsgeneticsCase-Control StudiesCell AdhesiongeneticsCell Adhesion Molecules, NeuronalgeneticsChromosomes, Human, Pair 5geneticsCohort StudiesGenetic MarkersgeneticsGenetic Predisposition to DiseasegeneticsGenetic VariationgeneticsGenome-Wide Association StudyGenotypeHumansPolymorphism, Single NucleotidegeneticsReproducibility of Results20081128200931820095190200951902009721902010921ppublish19404256NIHMS140827PMC294351110.1038/nature07999nature07999Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 2008;9:341–355.PMC275641418414403Autism and Developmental Disabilities Monitoring Network. 2007. 〈 http://www.cdc.gov/mmwr/pdf/ss/ss5601.pdf 〉 .Bailey A, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 1995;25:63–77.7792363Lauritsen MB, Pedersen CB, Mortensen PB. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychol. Psychiatry. 2005;46:963–971.16108999Sykes NH, Lamb JA. Autism: the quest for the genes. Expert Rev. Mol. Med. 2007;9:1–15.17764594Gupta AR, State MW. Recent advances in the genetics of autism. Biol. Psychiatry. 2007;61:429–437.16996486Freitag CM. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol. Psychiatry. 2007;12:2–22.17033636Veenstra-VanderWeele J, Cook EH., Jr. Molecular genetics of autism spectrum disorder. Mol. Psychiatry. 2004;9:819–832.15197396Vorstman JAS, et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol. Psychiatry. 2006;11:18–28.16205736Sebat J, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–449.PMC299350417363630Weiss LA, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 2008;358:667–675.18184952Kumar RA, et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 2008;17:628–638.18156158Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 2008;82:477–488.PMC242691318252227The Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678.PMC271928817554300Sklar P, et al. Whole-genome association study of bipolar disorder. Mol. Psychiatry. 2008;13:558–569.PMC377781618317468Alkelai A, et al. The XVth world congress of psychiatric genetics, October 7–11, 2007: rapporteur summaries of oral presentations. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2008;174B:233–277.18297693O'Donovan MC, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genet. 2008;40:1053–1055.18677311Ferreira MA, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nature Genet. 2008;40:1056–1058.PMC270378018711365Geschwind DH, et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am. J. Hum. Genet. 2001;69:463–466.PMC123532011452364Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J. Autism Dev. Disord. 1994;24:659–685.7814313Lord C, et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J. Autism Dev. Disord. 2000;30:205–223.11055457Martin ER, Monks SA, Warren LL, Kaplan NL. A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am. J. Hum. Genet. 2000;67:146–154.PMC128707310825280Chung RH, Morris RW, Zhang L, Li YJ, Martin ER. X-APL: an improved family-based test of association in the presence of linkage for the X chromosome. Am. J. Hum. Genet. 2007;80:59–68.PMC178530917160894de Bakker PI, et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 2008;17:R122–R128.PMC278235818852200Wang K, et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007;17:1665–1674.PMC204514917921354Kuhn RM, et al. The UCSC genome browser database: update 2009. Nucleic Acids Res. 2009;37:D755–D761.PMC268646318996895Siepel A, et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034–1050.PMC118221616024819Ovcharenko I, et al. Evolution and functional classification of vertebrate gene deserts. Genome Res. 2005;15:137–145.PMC54027915590943Abrahams BS, et al. Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Natl Acad. Sci. USA. 2007;104:17849–17854.PMC207701817978184Kools P, Vanhalst K, Van den Eynde E, van Roy F. The human cadherin-10 gene: complete coding sequence, predominant expression in the brain, and mapping on chromosome 5p13–14. FEBS Lett. 1999;452:328–334.10386616Visel A, Thaller C, Eichele G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 2004;32:D552–D556.PMC30876314681479Heinzen EL, et al. Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol. 2008;6:e1000001.PMC260593019222302Witte JS. Multiple prostate cancer risk variants on 8q24. Nature Genet. 2007;39:579–580.17460686Ghoussaini M, et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl. Cancer Inst. 2008;100:962–966.PMC290281918577746Kim HG, et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 2008;82:199–207.PMC225396118179900Szatmari P, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 2007;39:319–328.PMC486700817322880Arking DE, et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 2008;82:160–164.PMC225396818179894Alarcon M, et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 2008;82:150–159.PMC225395518179893Bakkaloglu B, et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 2008;82:165–173.PMC225397418179895Morrow EM, et al. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008;321:218–223.PMC258617118621663Redies C. Cadherins in the central nervous system. Prog. Neurobiol. 2000;61:611–648.10775799Simes RJ. An improved Bonferroni procedure for multiple tests of significance. Biometrika. 1986;73:751–754.Wang K, Li M, Bucan M. Pathway-based approaches for analysis of genomewide association studies. Am. J. Hum. Genet. 2007;81:1278–1283.PMC227635217966091Just MA, Cherkassky VL, Keller TA, Minshew NJ. Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain. 2004;127:1811–1821.15215213Koshino H, et al. fMRI investigation of working memory for faces in autism: visual coding and underconnectivity with frontal areas. Cereb. Cortex. 2008;18:289–300.PMC450015417517680Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137–145.18258309Courchesne E, Pierce K. Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr. Opin. Neurobiol. 2005;15:225–230.15831407Hughes JR. Autism: the first firm finding = underconnectivity? Epilepsy Behav. 2007;11:20–24.17531541Frith C. Is autism a disconnection disorder? Lancet Neurol. 2004;3:577.15380151Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr. Opin. Neurobiol. 2007;17:103–111.17275283Ma DQ, et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. doi:10.1111/j.1469-1809.2008.00523.x (in the press)PMC291841019456320