Title | Functional impact of global rare copy number variation in autism spectrum disorders. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Pinto, D, Pagnamenta, AT, Klei, L, Anney, R, Merico, D, Regan, R, Conroy, J, Magalhaes, TR, Correia, C, Abrahams, BS, Almeida, J, Bacchelli, E, Bader, GD, Bailey, AJ, Baird, G, Battaglia, A, Berney, T, Bolshakova, N, Bölte, S, Bolton, PF, Bourgeron, T, Brennan, S, Brian, J, Bryson, SE, Carson, AR, Casallo, G, Casey, J, H Y Chung, B, Cochrane, L, Corsello, C, Crawford, EL, Crossett, A, Cytrynbaum, C, Dawson, G, de Jonge, M, Delorme, R, Drmic, I, Duketis, E, Duque, F, Estes, A, Farrar, P, Fernandez, BA, Folstein, SE, Fombonne, E, Freitag, CM, Gilbert, J, Gillberg, C, Glessner, JT, Goldberg, J, Green, A, Green, J, Guter, SJ, Hakonarson, H, Heron, EA, Hill, M, Holt, R, Howe, JL, Hughes, G, Hus, V, Igliozzi, R, Kim, C, Klauck, SM, Kolevzon, A, Korvatska, O, Kustanovich, V, Lajonchere, CM, Lamb, JA, Laskawiec, M, Leboyer, M, Le Couteur, A, Leventhal, BL, Lionel, AC, Liu, X-Q, Lord, C, Lotspeich, L, Lund, SC, Maestrini, E, Mahoney, W, Mantoulan, C, Marshall, CR, McConachie, H, McDougle, CJ, McGrath, J, McMahon, WM, Merikangas, A, Migita, O, Minshew, NJ, Mirza, GK, Munson, J, Nelson, SF, Noakes, C, Noor, A, Nygren, G, Oliveira, G, Papanikolaou, K, Parr, JR, Parrini, B, Paton, T, Pickles, A, Pilorge, M, Piven, J, Ponting, CP, Posey, DJ, Poustka, A, Poustka, F, Prasad, A, Ragoussis, J, Renshaw, K, Rickaby, J, Roberts, W, Roeder, K, Rogé, B, Rutter, ML, Bierut, LJ, Rice, JP, Salt, J, Sansom, K, Sato, D, Segurado, R, Sequeira, AF, Senman, L, Shah, N, Sheffield, VC, Soorya, L, Sousa, I, Stein, O, Sykes, N, Stoppioni, V, Strawbridge, C, Tancredi, R, Tansey, K, Thiruvahindrapduram, B, Thompson, AP, Thomson, S, Tryfon, A, Tsiantis, J, van Engeland, H, Vincent, JB, Volkmar, F, Wallace, S, Wang, K, Wang, Z, Wassink, TH, Webber, C, Weksberg, R, Wing, K, Wittemeyer, K, Wood, S, Wu, J, Yaspan, BL, Zurawiecki, D, Zwaigenbaum, L, Buxbaum, JD, Cantor, RM, Cook, EH, Coon, H, Cuccaro, ML, Devlin, B, Ennis, S, Gallagher, L, Geschwind, DH, Gill, M, Haines, JL, Hallmayer, J, Miller, J, Monaco, AP, Nurnberger, JI, Paterson, AD, Pericak-Vance, MA, Schellenberg, GD, Szatmari, P, Vicente, AM, Vieland, VJ, Wijsman, EM, Scherer, SW, Sutcliffe, JS, Betancur, C |
Journal | Nature |
Volume | 466 |
Issue | 7304 |
Pagination | 368-72 |
Date Published | 2010 Jul 15 |
ISSN | 1476-4687 |
Keywords | Case-Control Studies, Cell Movement, Child, Child Development Disorders, Pervasive, Cytoprotection, DNA Copy Number Variations, Europe, Gene Dosage, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Signal Transduction, Social Behavior |
Abstract | 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. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), 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. |
DOI | 10.1038/nature09146 |
Alternate Journal | Nature |
PubMed ID | 20531469 |
PubMed Central ID | PMC3021798 |
Grant List | MH57881 / MH / NIMH NIH HHS / United States P50 HD055782 / HD / NICHD NIH HHS / United States R01 MH061009-05 / MH / NIMH NIH HHS / United States R01 NS049261 / NS / NINDS NIH HHS / United States MH066673 / MH / NIMH NIH HHS / United States R37 MH057881 / MH / NIMH NIH HHS / United States P01 HD035465 / HD / NICHD NIH HHS / United States U19 HD035469-10 / HD / NICHD NIH HHS / United States U01 HG004422-02 / HG / NHGRI NIH HHS / United States NS049261 / NS / NINDS NIH HHS / United States P01 CA089392-08 / CA / NCI NIH HHS / United States P01 NS026630 / NS / NINDS NIH HHS / United States MC_U137761446 / / Medical Research Council / United Kingdom R01 MH081754-01 / MH / NIMH NIH HHS / United States U19 HD035469-09 / HD / NICHD NIH HHS / United States MH55284 / MH / NIMH NIH HHS / United States R01 MH055284-04 / MH / NIMH NIH HHS / United States MH080647 / MH / NIMH NIH HHS / United States R01 NS042165-05 / NS / NINDS NIH HHS / United States MH061009 / MH / NIMH NIH HHS / United States HD055782 / HD / NICHD NIH HHS / United States R01 MH061009 / MH / NIMH NIH HHS / United States U19 HD035469 / HD / NICHD NIH HHS / United States MH081754 / MH / NIMH NIH HHS / United States P50 HD055748-03 / HD / NICHD NIH HHS / United States P50 HD055748-01 / HD / NICHD NIH HHS / United States P01 CA089392 / CA / NCI NIH HHS / United States T32 MH065215 / MH / NIMH NIH HHS / United States AS2077 / / Autism Speaks / United States U10 MH066766 / MH / NIMH NIH HHS / United States R01 NS042165 / NS / NINDS NIH HHS / United States U19 HD035469-06 / HD / NICHD NIH HHS / United States MH66766 / MH / NIMH NIH HHS / United States MH52708 / MH / NIMH NIH HHS / United States R01 MH057881 / MH / NIMH NIH HHS / United States NS042165 / NS / NINDS NIH HHS / United States R01 MH080647-11 / MH / NIMH NIH HHS / United States P50 HD055748 / HD / NICHD NIH HHS / United States AS7462 / / Autism Speaks / United States / / Canadian Institutes of Health Research / Canada U01 HG004422 / HG / NHGRI NIH HHS / United States R01 DA019963-02 / DA / NIDA NIH HHS / United States P01 NS026630-15 / NS / NINDS NIH HHS / United States R01 DA013423-05 / DA / NIDA NIH HHS / United States P50 HD055751 / HD / NICHD NIH HHS / United States R01 MH052708-05 / MH / NIMH NIH HHS / United States R01 DA019963 / DA / NIDA NIH HHS / United States R01 DA013423 / DA / NIDA NIH HHS / United States U54 MH066673-05 / MH / NIMH NIH HHS / United States P50 HD055784 / HD / NICHD NIH HHS / United States P50 HD055751-01 / HD / NICHD NIH HHS / United States U10 MH066766-05 / MH / NIMH NIH HHS / United States R01 MH080647 / MH / NIMH NIH HHS / United States HD055784 / HD / NICHD NIH HHS / United States P01 HD035465-01S1 / HD / NICHD NIH HHS / United States R01 MH081754 / MH / NIMH NIH HHS / United States R01 MH055284 / MH / NIMH NIH HHS / United States R01 MH057881-02 / MH / NIMH NIH HHS / United States UL1 TR000448 / TR / NCATS NIH HHS / United States MH06359 / MH / NIMH NIH HHS / United States R01 DA019963-01A2 / DA / NIDA NIH HHS / United States 075491/Z/04 / / Wellcome Trust / United Kingdom G0601030 / / Medical Research Council / United Kingdom R01 DA019963-03 / DA / NIDA NIH HHS / United States NS026630 / NS / NINDS NIH HHS / United States HD35465 / HD / NICHD NIH HHS / United States U54 MH066673 / MH / NIMH NIH HHS / United States R01 NS049261-02 / NS / NINDS NIH HHS / United States P50 HD055748-02 / HD / NICHD NIH HHS / United States U19 HD035469-08 / HD / NICHD NIH HHS / United States U19 HD035469-07 / HD / NICHD NIH HHS / United States HD055751 / HD / NICHD NIH HHS / United States P50 HD055782-04 / HD / NICHD NIH HHS / United States |
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