Synaptic, transcriptional and chromatin genes disrupted in autism.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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; Shih-Chen, F; Aleksic, B; Biscaldi, M; Bolton, PF; Brownfeld, JM; Cai, J; Campbell, NG; Carracedo, A; Chahrour, MH; Chiocchetti, AG; Coon, H; Crawford, EL; Curran, SR; Dawson, G; Duketis, E; Fernandez, BA; Gallagher, L; Geller, E; Guter, SJ; Hill, RS; Ionita-Laza, J; Jimenz Gonzalez, P; Kilpinen, H; Klauck, SM; Kolevzon, A; Lee, I; Lei, I; Lei, J; Lehtimäki, T; Lin, C-F; Ma'ayan, A; Marshall, CR; McInnes, AL; Neale, B; Owen, MJ; Ozaki, N; Parellada, M; Parr, JR; Purcell, S; Puura, K; Rajagopalan, D; Rehnström, K; Reichenberg, A; Sabo, A; Sachse, M; Sanders, SJ; Schafer, C; Schulte-Rüther, M; Skuse, D; Stevens, C; Szatmari, P; Tammimies, K; Valladares, O; Voran, A; Li-San, W; Weiss, LA; Willsey, AJ; Yu, TW; Yuen, RKC; DDD Study, ; Homozygosity Mapping Collaborative for Autism, ; UK10K Consortium, ; Cook, EH; Freitag, CM; Gill, M; Hultman, CM; Lehner, T; Palotie, A; Schellenberg, GD; Sklar, P; State, MW; Sutcliffe, JS; Walsh, CA; Scherer, SW; Zwick, ME; Barett, JC; Cutler, DJ; Roeder, K; Devlin, B; Daly, MJ; Buxbaum, JD

Published Date

  • November 13, 2014

Published In

Volume / Issue

  • 515 / 7526

Start / End Page

  • 209 - 215

PubMed ID

  • 25363760

Pubmed Central ID

  • PMC4402723

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/nature13772


  • eng

Conference Location

  • England