Publication
Synaptic, transcriptional and chromatin genes disrupted in autism.
De Rubeis Silvia, He Xin, Goldberg Arthur P, Poultney Christopher S, Samocha Kaitlin, Cicek A Erucment, Kou Yan, Liu Li, Fromer Menachem, Walker Susan, Singh Tarinder, Klei Lambertus, Kosmicki Jack, Shih-Chen Fu, Aleksic Branko, Biscaldi Monica, Bolton Patrick F, Brownfeld Jessica M, Cai Jinlu, Campbell Nicholas G, Carracedo Angel, Chahrour Maria H, Chiocchetti Andreas G, Coon Hilary, Crawford Emily L, Curran Sarah R, Dawson Geraldine, Duketis Eftichia, Fernandez Bridget A, Gallagher Louise, Geller Evan, Guter Stephen J, Hill R Sean, Ionita-Laza Juliana, Jimenz Gonzalez Patricia, Kilpinen Helena, Klauck Sabine M, Kolevzon Alexander, Lee Irene, Lei Irene, Lei Jing, Lehtimäki Terho, Lin Chiao-Feng, Ma'ayan Avi, Marshall Christian R, McInnes Alison L, Neale Benjamin, Owen Michael J, Ozaki Noriio, Parellada Mara, Parr Jeremy R, Purcell Shaun, Puura Kaija, Rajagopalan Deepthi, Rehnström Karola, Reichenberg Abraham, Sabo Aniko, Sachse Michael, Sanders Stephan J, Schafer Chad, Schulte-Rüther Martin, Skuse David, Stevens Christine, Szatmari Peter, Tammimies Kristiina, Valladares Otto, Voran Annette, Li-San Wang, Weiss Lauren A, Willsey A Jeremy, Yu Timothy W, Yuen Ryan K C, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook Edwin H, Freitag Christine M, Gill Michael, Hultman Christina M, Lehner Thomas, Palotie Aaarno, Schellenberg Gerard D, Sklar Pamela, State Matthew W, Sutcliffe James S, Walsh Christiopher A, Scherer Stephen W, Zwick Michael E, Barett Jeffrey C, Cutler David J, Roeder Kathryn, Devlin Bernie, Daly Mark J, Buxbaum Joseph D
# Synaptic, Transcriptional and Chromatin Genes Disrupted in Autism
This study investigated the genetic basis of autism spectrum disorder through exome sequencing of 3,871 autism cases and 9,937 controls. The analysis identified 22 autosomal genes significantly associated with autism at false discovery rate <0.05, plus an additional 107 genes strongly enriched for autism risk at FDR <0.30. These 107 genes exhibited unusual evolutionary constraint against mutations and carried de novo loss-of-function mutations in over 5% of autistic subjects.
The implicated genes predominantly encode proteins involved in three major pathways: synaptic formation, transcriptional regulation, and chromatin remodelling. Notably, the findings include voltage-gated ion channels that regulate action potential propagation, neuronal pacemaking, and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers. These genes are particularly enriched for mediators of lysine methylation and demethylation modifications of histones, suggesting that epigenetic mechanisms play a central role in autism's genetic architecture.
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.