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

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TitleIndividual common variants exert weak effects on the risk for autism spectrum disorders.
Publication TypeJournal Article
Year of Publication2012
AuthorsAnney, R, Klei, L, Pinto, D, Almeida, J, Bacchelli, E, Baird, G, Bolshakova, N, Bölte, 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, X-Q, 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, Rogé, 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, SW, 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
JournalHum Mol Genet
Volume21
Issue21
Pagination4781-92
Date Published2012 Nov 01
ISSN1460-2083
KeywordsAlleles, Child, Child Development Disorders, Pervasive, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Language Development, Male, Membrane Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Risk Factors
Abstract

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.

DOI10.1093/hmg/dds301
Alternate JournalHum. Mol. Genet.
PubMed ID22843504
PubMed Central IDPMC3471395
Grant ListP50 HD055782 / HD / NICHD NIH HHS / United States
MH066673 / MH / NIMH NIH HHS / United States
NS049261 / NS / NINDS NIH HHS / United States
MH55284 / MH / NIMH NIH HHS / United States
MH080647 / MH / NIMH NIH HHS / United States
MH061009 / MH / NIMH NIH HHS / United States
HD055782 / HD / NICHD NIH HHS / United States
MH081754 / MH / NIMH NIH HHS / United States
HD055748 / HD / NICHD NIH HHS / United States
/ / Medical Research Council / United Kingdom
MH66766 / MH / NIMH NIH HHS / United States
MH52708 / MH / NIMH NIH HHS / United States
AS7569 / / Autism Speaks / United States
NS042165 / NS / NINDS NIH HHS / United States
HD035469 / HD / NICHD NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
P50 HD055751 / HD / NICHD NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
HD055784 / HD / NICHD NIH HHS / United States
MH057881 / MH / NIMH NIH HHS / United States
MH06359 / MH / NIMH NIH HHS / United States
R01 MH094400 / MH / NIMH NIH HHS / United States
075491/Z/04 / / Wellcome Trust / United Kingdom
G0601030 / / Medical Research Council / United Kingdom
NS026630 / NS / NINDS NIH HHS / United States
HD055751 / HD / NICHD NIH HHS / United States
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