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Author Notes:

Correspondence should be addressed to J.D.B. (Email: joseph.buxbaum@mssm.edu) or M.J.D. (Email:mjdaly@broadinstitute.org)

Study conception and design: J.D.B., D.J.C., M.J.D., S.D.R., B.D., M.F., A.P.G., X.H., T.L., C.S.P., K.Ro., M.W.S. and M.E.Z.

Data analysis: J.C.B., P.F.B., J.D.B., J.C., AE.C, D.J.C., M.J.D., S.D.R., B.D., M.F., SC.F., A.P.G., X.H., L.K., J.K., Y.K., L.L., A.M., C.S.P., S.P., K.Ro., K.S., C.S., T.S., C.St., S.W., L.W. and M.E.Z.

Contribution of samples, WES data or analytical tools: B.A., J.C.B., M.B., P.F.B., J.D.B., J.C., N.J.C., A.C., M.H.C., A.G.C., AE.C, H.C., E.L.C., L.C., S.R.C., D.J.C., M.J.D., G.D., S.D.R., B.D., E.D., B.A.F., C.M.F., M.F., L.G., E.G., M.G., A.P.G., S.J.G., X.H., R.H., C.M.H., I.I-L., P.J.G., H.K., S.M.K., L.K., A.K., J.K., Y.K., I.L., J.L., T.Le., C.L., L.L., A.M., C.R.M., A.L.McI., B.N., M.J.O., N.O., A.P., M.P., J.R.P., C.S.P., S.P., K.P., D.R., K.R., A.R., K.Ro., A.S., M.S., K.S., S.J.S., C.S., G.D.S., S.W.S., M.S-R., T.S., P.S., D.S., M.W.S., C.St., J.S.S., P.Sz., K.T., O.V., A.V., S.W., C.A.W., L.W., L.A.W., J.A.W., T.W.Y., R.KC.Y., M.E.Z.

Writing of the paper: J.C.B., J.D.B., E.H.C., D.J.C., M.J.D., S.D.R., B.D., M.G., A.P.G., X.H., C.S.P., K.Ro., S.W.S., M.E.Z.

Leads of ASC committees: J.D.B., E.H.C., M.J.D., B.D., M.G., K.Ro., M.W.S., J.S.S., M.E.Z.

Administration of ASC: J.M.B

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 timely assistance of Dan 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, without whose participation this study would not have been possible.

The authors have no competing interests

Research Funding:

This work was supported by 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 RO1MH083565 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 Hospital, Crumlin, The Meath Foundation, AMNCH, Tallaght The Health Research Board, Ireland Autism Speaks, US.

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 an UK 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).


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
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Synaptic, transcriptional and chromatin genes disrupted in autism

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Journal Title:



Volume 515, Number 7526


, Pages 209-U119

Type of Work:

Article | Final Publisher PDF


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.

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