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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
New data included in this manuscript have been deposited at dbGAP merged with our published data under accession number phs000298.v1.p1 and is available for download at (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000298.v1.p1).
This work was supported by National Institutes of Health (NIH) grants U01MH100233, U01MH100209, U01MH100229 and U01MH100239 to the Autism Sequencing Consortium. Sequencing at Broad Institute was supported by NIH grants R01MH089208 (M.J.D.) and new sequencing by U54 HG003067 (S. Gabriel, E. Lander). Other funding includes NIH R01 MH089482, R37 MH057881 (B.D. and K.R.), R01 MH061009 (J.S.S.), UL1TR000445 (NCAT to VUMC); P50 HD055751 (E.H.C.); MH089482 (J.S.S.), NIH RO1 MH083565 and RC2MH089952 (C.A.W.), NIMH MH095034 (P.S), MH077139 (P.F. Sullivan); 5UL1 RR024975 and P30 HD15052. The DDD Study is funded by HICF-1009-003 and WT098051. UK10K is funded by WT091310. We also acknowledge The National Children’s Research Foundation, Our Lady’s Children’s Hospital, Crumlin; The Meath Foundation; AMNCH, Tallaght; The Health Research Board, Ireland and Autism Speaks, U.S.A. C.A.W. is an Investigator of the Howard Hughes Medical Institute. S.D.R., A.P.G., C.S.P., Y.K. and S.-C.F. are Seaver fellows, supported by the Seaver foundation. A.P.G. is also supported by the Charles and Ann Schlaifer Memorial Fund. P.F.B. is supported by a UK National Institute for Health Research (NIHR) Senior Investigator award and the NIHR Biomedical Research Centre in Mental Health at the South London & Maudsley Hospital. A.C. is supported by María José Jove Foundation and the grant FIS PI13/01136 of the Strategic Action from Health Carlos III Institute (FEDER). This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. We acknowledge the assistance of D. Hall and his team at National Database for Autism Research. We thank Jian Feng for providing a list of targets of both RBFOX1 and H3K4me3. We thank M. Potter for data coordination; K. Moore and J. Reichert for technical assistance; and, S. Lindsay for helping with molecular validation. We acknowledge the clinicians and organizations that contributed to samples used in this study. Finally, we are grateful to the many families whose participation made this study possible.
Extended data figures
Extended data tables
This file contains Supplementary Table 1.
This file contains Supplementary Table 2.
This file contains Supplementary Table 3.
This file contains Supplementary Table 4.
This file contains Supplementary Table 5.
This file contains Supplementary Table 6.
About this article
Annual Review of Medicine (2019)