Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

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TitleConvergence of genes and cellular pathways dysregulated in autism spectrum disorders.
Publication TypeJournal Article
Year of Publication2014
AuthorsPinto, D, Delaby, E, Merico, D, Barbosa, M, Merikangas, A, Klei, L, Thiruvahindrapuram, B, Xu, X, Ziman, R, Wang, Z, Vorstman, JAS, Thompson, A, Regan, R, Pilorge, M, Pellecchia, G, Pagnamenta, AT, Oliveira, B, Marshall, CR, Magalhaes, TR, Lowe, JK, Howe, JL, Griswold, AJ, Gilbert, J, Duketis, E, Dombroski, BA, De Jonge, MV, Cuccaro, M, Crawford, EL, Correia, CT, Conroy, J, Conceição, IC, Chiocchetti, AG, Casey, JP, Cai, G, Cabrol, C, Bolshakova, N, Bacchelli, E, Anney, R, Gallinger, S, Cotterchio, M, Casey, G, Zwaigenbaum, L, Wittemeyer, K, Wing, K, Wallace, S, van Engeland, H, Tryfon, A, Thomson, S, Soorya, L, Rogé, B, Roberts, W, Poustka, F, Mouga, S, Minshew, N, L McInnes, A, McGrew, SG, Lord, C, Leboyer, M, Le Couteur, AS, Kolevzon, A, González, PJiménez, Jacob, S, Holt, R, Guter, S, Green, J, Green, A, Gillberg, C, Fernandez, BA, Duque, F, Delorme, R, Dawson, G, Chaste, P, Café, C, Brennan, S, Bourgeron, T, Bolton, PF, Bölte, S, Bernier, R, Baird, G, Bailey, AJ, Anagnostou, E, Almeida, J, Wijsman, EM, Vieland, VJ, Vicente, AM, Schellenberg, GD, Pericak-Vance, M, Paterson, AD, Parr, JR, Oliveira, G, Nurnberger, JI, Monaco, AP, Maestrini, E, Klauck, SM, Hakonarson, H, Haines, JL, Geschwind, DH, Freitag, CM, Folstein, SE, Ennis, S, Coon, H, Battaglia, A, Szatmari, P, Sutcliffe, JS, Hallmayer, J, Gill, M, Cook, EH, Buxbaum, JD, Devlin, B, Gallagher, L, Betancur, C, Scherer, SW
JournalAm J Hum Genet
Date Published2014 May 01
KeywordsChild, Child Development Disorders, Pervasive, DNA Copy Number Variations, Female, Gene Regulatory Networks, Humans, Male, Metabolic Networks and Pathways, Multigene Family, Pedigree, Sequence Deletion

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.

Alternate JournalAm J Hum Genet
PubMed ID24768552
PubMed Central IDPMC4067558
Grant ListR01 MH094714 / MH / NIMH NIH HHS / United States
U54 HD083091 / HD / NICHD NIH HHS / United States
R01 MH094382 / MH / NIMH NIH HHS / United States
/ / Medical Research Council / United Kingdom
/ / Canadian Institutes of Health Research / Canada
090532 / / Wellcome Trust / United Kingdom
R01 MH094400 / MH / NIMH NIH HHS / United States
R01 MH094293 / MH / NIMH NIH HHS / United States
T32 GM082773 / GM / NIGMS NIH HHS / United States
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