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

Richard Anney, Lambertus Klei, Dalila Pinto, Joana Almeida, Elena Bacchelli, Gillian Baird, Nadia Bolshakova, Sven Bölte, Patrick F. Bolton, Thomas Bourgeron, Sean Brennan, Jessica Brian, Jillian Casey, Judith Conroy, Catarina Correia, Christina Corsello, Emily L. Crawford, Maretha de Jonge, Richard Delorme, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Eric Fombonne, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Andrew Green, Jonathan Green, Stephen J. Guter, Elizabeth A. Heron, Richard Holt, Jennifer L. Howe, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Suma Jacob, Graham P. Kenny, Cecilia Kim, Alexander Kolevzon, Vlad Kustanovich, Clara M. Lajonchere, Janine A. Lamb, Miriam Law-Smith, Marion Leboyer, Ann Le Couteur, Bennett L. Leventhal, Xiao-Qing Liu, Frances Lombard, Catherine Lord, Linda Lotspeich, Sabata C. Lund, Tiago R. Magalhaes, Carine Mantoulan, Christopher J. McDougle, Nadine M. Melhem, Alison Merikangas, Nancy J. Minshew, Ghazala K. Mirza, Jeff Munson, Carolyn Noakes, Gudrun Nygren, Katerina Papanikolaou, Alistair T. Pagnamenta, Barbara Parrini, Tara Paton, Andrew Pickles, David J. Posey, Fritz Poustka, Jiannis Ragoussis, Regina Regan, Wendy Roberts, Kathryn Roeder, Bernadette Roge, Michael L. Rutter, Sabine Schlitt, Naisha Shah, Val C. Sheffield, Latha Soorya, Inês Sousa, Vera Stoppioni, Nuala Sykes, Raffaella Tancredi, Ann P. Thompson, Susanne Thomson, Ana Tryfon, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar, JAS Vorstman, Simon Wallace, Kirsty Wing, Kerstin Wittemeyer, Shawn Wood, Danielle Zurawiecki, Lonnie Zwaigenbaum, Anthony J. Bailey, Agatino Battaglia, Rita M. Cantor, Hilary Coon, Michael L. Cuccaro, Geraldine Dawson, Sean Ennis, Christine M. Freitag, Daniel H. Geschwind, Jonathan L. Haines, Sabine M. Klauck, William M. McMahon, Elena Maestrini, Judith Miller, Anthony P. Monaco, Stanley F. Nelson, John I. Nurnberger, Guiomar Oliveira, Jeremy R. Parr, Margaret A. Pericak-Vance, Joseph Piven, Gerard D. Schellenberg, Stephen W. Scherer, Astrid M. Vicente, Thomas H. Wassink, Ellen M. Wijsman, Catalina Betancur, Joseph D. Buxbaum, Edwin H. Cook, Louise Gallagher, Michael Gill, Joachim Hallmayer, Andrew D. Paterson, James S. Sutcliffe, Peter Szatmari, Veronica J. Vieland, Hakon Hakonarson, Bernie Devlin

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.