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Individual common variants exert weak effects on the risk for autism spectrum disorderspi

Lookup NU author(s): Professor Ann Le Couteur, Professor Jeremy Parr


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While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm 1). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Publication metadata

Author(s): Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JAS, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer S, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, Devlin B

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2012

Volume: 21

Issue: 21

Pages: 4781-4792

Print publication date: 26/07/2012

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/dds301


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Funder referenceFunder name
AGP: Autism Speaks (USA)
Assistance Publique - Hopitaux de Paris (France)
Centre for Applied Genomics (Canada)
Fondation FondaMental (France)
Fundacao Calouste Gulbenkian (Portugal)
Hilibrand Foundation (USA)
Italian Ministry of Health
John P Hussman Foundation (USA)
Ontario Ministry of Research and Innovation (Canada)
Science Foundation Ireland
Swedish Science Council
Trinity Centre for High Performance Computing
University of Toronto (Canada)
Utah Autism Foundation (USA)
Autism Speaks
Autism Speaks UK
Canada Foundation for Innovation/Ontario Innovation Trust
Cnadian Institutes for Health Research (CIHR)
Fondation de France
Fondation Orange (France)
Fondation pour la Recherche Medicale (France)
Fundacao para a Ciencia e Tecnologia (Portugal)
Genome Canada/Ontario Genomics Institute
Hospital for Sick Children Foundation
INSERM (France)
Institut Pasteur (France)
McLaughlin Centre (Canada)
Medical Research Council (MRC; UK)
National Childrens Research Centre (Ireland)
Seaver Foundation (USA)
075491/Z/04Wellcome Trust (UK)
AUT/2006/1Health Research Board (HRB; Ireland)
AUT/2006/2Health Research Board (HRB; Ireland)
825.06.031Netherlands Organization for Scientific Research
HD035469US National Institutes of Health (NIH)
HD055748US National Institutes of Health (NIH)
HD055782US National Institutes of Health (NIH)
MH057881US National Institutes of Health (NIH)
MH061009US National Institutes of Health (NIH)
MH06359US National Institutes of Health (NIH)
MH066673US National Institutes of Health (NIH)
MH52708US National Institutes of Health (NIH)
HD055751US National Institutes of Health (NIH)
HD055784US National Institutes of Health (NIH)
MH080647US National Institutes of Health (NIH)
MH081754US National Institutes of Health (NIH)
MH55284US National Institutes of Health (NIH)
MH66766US National Institutes of Health (NIH)
NS026630US National Institutes of Health (NIH)
PD/2006/48Health Research Board (HRB; Ireland)
Po 255/17-4Deutsche Forschungsgemeinschaft (Germany)
NS042165US National Institutes of Health (NIH)
NS049261US National Institutes of Health (NIH)
TMF/DA/5801Royal Netherlands Academy of Arts and Sciences