Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Richard J.L. Anney, Elaine M. Kenny, Colm O'Dushlaine, Brian L. Yaspan, Elena Parkhomenka, Joseph D. Buxbaum, James Sutcliffe, Michael Gill, Louise Gallagher, Anthony J. Bailey, Bridget A. Fernandez, Peter Szatmari, Stephen W. Scherer, Andrew Patterson, Christian R. Marshall, Dalila Pinto, John B. Vincent, Eric Fombonne, Catalina Betancur, Richard DelormeMarion Leboyer, Thomas Bourgeron, Carine Mantoulan, Bernadette Roge, Mäité Tauber, Christine M. Freitag, Fritz Poustka, Eftichia Duketis, Sabine M. Klauck, Annemarie Poustka, Katerina Papanikolaou, John Tsiantis, Nadia Bolshakova, Sean Brennan, Gillian Hughes, Jane McGrath, Alison Merikangas, Sean Ennis, Andrew Green, Jillian P. Casey, Judith M. Conroy, Regina Regan, Naisha Shah, Elena Maestrini, Elena Bacchelli, Fiorella Minopoli, Vera Stoppioni, Agatino Battaglia, Roberta Igliozzi, Suma Jacob, Autism Genome Project

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.

Original languageEnglish (US)
Pages (from-to)1082-1089
Number of pages8
JournalEuropean Journal of Human Genetics
Volume19
Issue number10
DOIs
StatePublished - Oct 2011

Bibliographical note

Funding Information:
We gratefully acknowledge the families participating in the study and the main funders of the AGP: Autism Speaks (USA), the Health Research Board (HRB, Ireland; AUT/2006/1, AUT/2006/2, PD/2006/48), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH Grants: HD055751, HD055782, HD055784, MH52708, MH55284, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institutes for Health Research (CIHR), Assistance Publique – Hôpitaux de Paris (France), Autism Speaks UK, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (Grant: Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundac¸ão Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundac¸ão para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19 October 2001), the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). DP is supported by fellowships from the Royal Netherlands Academy of Arts and Sciences (TMF/DA/5801) and the Netherlands Organization for Scientific Research (Rubicon 825.06.031). SWS holds the GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children (Canada).

Publisher Copyright:
© 2011 Macmillan Publishers Limited All rights reserved.

Keywords

  • autism
  • family-based association test
  • gene ontology
  • genome-wide association analysis
  • pathway analysis

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