Functional impact of global rare copy number variation in autism spectrum disorders.

New CAR Research Sheds Light on

 

Universal Screening for Autism in Toddlers

TitleFunctional impact of global rare copy number variation in autism spectrum disorders.
Publication TypeJournal Article
Year of Publication2010
AuthorsPinto, 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
JournalNature
Volume466
Issue7304
Pagination368-72
Date Published2010 Jul 15
ISSN1476-4687
KeywordsCase-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.

DOI10.1038/nature09146
Alternate JournalNature
PubMed ID20531469
PubMed Central IDPMC3021798
Grant ListMH57881 / 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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