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Synaptic, transcriptional and chromatin genes disrupted in autism

Lookup NU author(s): Professor Jeremy Parr


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The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Publication metadata

Author(s): De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Fu SC, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai JL, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Crooks L, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza I, Gonzalez PJ, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei J, Lehtimaki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Wang LS, Weiss LA, Willsey AJ, Yu TW, Yuen RKC, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Skiar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barrett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD, DDD Study, Homozygosity Mapping Collaborative, UK10K Consortium, Autism Sequencing Consortium

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2014

Volume: 515

Issue: 7526

Pages: 209-U119

Print publication date: 13/11/2014

Online publication date: 29/10/2014

Acceptance date: 18/08/2014

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group


DOI: 10.1038/nature13772


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Funder referenceFunder name
Maria Jose Jove Foundation
Charles and Ann Schlaifer Memorial Fund
NIHR Biomedical Research Centre in Mental Health at the South London&Maudsley Hospital
UK National Institute for Health Research (NIHR) Senior Investigator award
5UL1 RR024975NIH
FIS PI13/01136Strategic Action from Health Carlos III Institute (FEDER)
P30 HD15052NIH
R37 MH057881NIH
P50 HD055751NIH
U01MH100209National Institutes of Health (NIH)
U01MH100229National Institutes of Health (NIH)
U01MH100233National Institutes of Health (NIH)
U01MH100239National Institutes of Health (NIH)
U54 HG003067NIH grants
R01 MH061009NIH
R01 MH089482NIH
R01MH089208NIH grants