Journal
NATURE
Volume 466, Issue 7304, Pages 368-372Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09146
Keywords
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Categories
Funding
- Autism Genome Project Consortium (AGP): Autism Speaks (USA)
- Health Research Board (HRB
- Ireland)
- Medical Research Council (MRC
- UK)
- Genome Canada/Ontario Genomics Institute
- Hilibrand Foundation (USA)
- US National Institutes of Health (NIH) [HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261]
- Canadian Institute for Advanced Research (CIFAR)
- Canadian Institutes for Health Research (CIHR)
- Assistance Publique-Hopitaux de Paris (France)
- Autistica
- Canada Foundation for Innovation/Ontario Innovation Trust
- Deutsche Forschungsgemeinschaft (Germany) [Po 255/17-4]
- EC
- Fundacao Calouste Gulbenkian (Portugal)
- Fondation de France
- Fondation FondaMental (France)
- Fondation Orange (France)
- Fondation pour la Recherche Medicale (France)
- Fundacao para a Ciencia e Tecnologia (Portugal)
- Hospital for Sick Children Foundation
- University of Toronto (Canada)
- INSERM (France)
- Institut Pasteur (France)
- Italian Ministry of Health [181]
- John P Hussman Foundation (USA)
- McLaughlin Centre (Canada)
- Ontario Ministry of Research and Innovation (Canada)
- Seaver Foundation (USA)
- Swedish Science Council
- Centre for Applied Genomics (Canada)
- Utah Autism Foundation (USA)
- Wellcome Trust (UK) [075491/Z/04]
- Royal Netherlands Academy of Arts and Sciences [TMF/DA/5801]
- Netherlands Organization for Scientific Research [825.06.031]
- GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto
- Hospital for Sick Children (Canada)
- MRC [G0601030, MC_U137761446] Funding Source: UKRI
- Medical Research Council [MC_U137761446, G0601030, G9817803B] Funding Source: researchfish
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The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours(1). Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability(2). Although ASDs are known to be highly heritable (similar to 90%)(3), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P=0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P=3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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