Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Dalila Pinto, Elsa Delaby, Daniele Merico, Mafalda Barbosa, Alison Merikangas, Lambertus Klei, Bhooma Thiruvahindrapuram, Xiao Xu, Robert Ziman, Zhuozhi Wang, Jacob A S Vorstman, Ann Thompson, Regina Regan, Marion Pilorge, Giovanna Pellecchia, Alistair T. Pagnamenta, Bárbara Oliveira, Christian R. Marshall, Tiago R. Magalhaes, Jennifer K. LoweJennifer L. Howe, Anthony J. Griswold, John Gilbert, Eftichia Duketis, Beth A. Dombroski, Maretha V. De Jonge, Michael Cuccaro, Emily L. Crawford, Catarina T. Correia, Judith Conroy, Inês C. Conceição, Andreas G. Chiocchetti, Jillian P. Casey, Guiqing Cai, Christelle Cabrol, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Steven Gallinger, Michelle Cotterchio, Graham Casey, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Kirsty Wing, Simon Wallace, Herman Van Engeland, Ana Tryfon, Susanne Thomson, Latha Soorya, Bernadette Rogé, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy Minshew, L. Alison McInnes, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann S. Le Couteur, Alexander Kolevzon, Patricia Jiménez González, Suma Jacob, Richard Holt, Stephen Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Pauline Chaste, Cátia Café, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony J. Bailey, Evdokia Anagnostou, Joana Almeida, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Gerard D. Schellenberg, Margaret Pericak-Vance, Andrew D. Paterson, Jeremy R. Parr, Guiomar Oliveira, John I. Nurnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, Hakon Hakonarson, Jonathan L. Haines, Daniel H. Geschwind, Christine M. Freitag, Susan E. Folstein, Sean Ennis, Hilary Coon, Agatino Battaglia, Peter Szatmari, James S. Sutcliffe, Joachim Hallmayer, Michael Gill, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Louise Gallagher, Catalina Betancur, Stephen W. Scherer

Research output: Contribution to journalArticlepeer-review

495 Scopus citations


Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10-5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10-15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Original languageEnglish (US)
Pages (from-to)677-694
Number of pages18
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - May 1 2014

Bibliographical note

Funding Information:
The authors thank the main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland; AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR). Additional support for individual groups is shown in the Supplemental Acknowledgments . D.P. is the Abraham & Mildred Goldstein Seaver Center Faculty Fellow, J.D.B. holds the G. Harold and Leila Y. Mathers Professorship, C.B. is the recipient of a NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation, and S.W.S. holds the GlaxoSmithKline-CIHR Pathfinder Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. E.H.C. is an advisor of Seaside Therapeutics, G.D. is a member of the Scientific Advisory Board at Integragen Inc., and S.W.S. is an advisor to Population Diagnostics and advisor and founder of YouNique Genomics. D.P., P.S., J.S.S., J.H., M.G., E.H.C., J.D.B., B.D., L.G., C.B., and S.W.S were leading contributors to the design and analysis of this study, and D.P., E. Delaby, D.M., M.B., J.D.B., B.D., L.G., C.B., and S.W.S wrote the manuscript.


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