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

Authors:
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 J A S 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

Hum Mol Genet 2012 Nov 26;21(21):4781-92. Epub 2012 Jul 26.

Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

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.

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Source
http://dx.doi.org/10.1093/hmg/dds301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471395PMC
November 2012
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