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Nature Research, Nature, 7526(515), p. 209-215, 2014

DOI: 10.1038/nature13772

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Synaptic, transcriptional and chromatin genes disrupted in autism.

Journal article published in 2014 by Silvia De Rubeis, Arthur P. Goldberg, Xin He, Christopher S. Poultney, A. Erucment Cicek, A. Ercument Cicek, Kaitlin Samocha ORCID, Yan Kou, Shih-Chen Fu, Branko Aleksic, Li Liu, Monica Biscaldi, Patrick F. Bolton, Goldberg Ap, Menachem Fromer and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.