期刊
NATURE
卷 515, 期 7526, 页码 209-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature13772
关键词
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资金
- National Institutes of Health (NIH) [U01MH100233, U01MH100209, U01MH100229, U01MH100239]
- NIH grants [R01MH089208, U54 HG003067]
- NIH [R01 MH089482, R37 MH057881, R01 MH061009, UL1TR000445, P50 HD055751, MH089482, NIH RO1 MH083565, RC2MH089952, NIMH MH095034, MH077139, 5UL1 RR024975, P30 HD15052]
- Charles and Ann Schlaifer Memorial Fund
- UK National Institute for Health Research (NIHR) Senior Investigator award
- NIHR Biomedical Research Centre in Mental Health at the South LondonAMP
- Maudsley Hospital
- Maria Jose Jove Foundation
- Strategic Action from Health Carlos III Institute (FEDER) [FIS PI13/01136]
- [HICF-1009-003]
- [WT098051]
- [WT091310]
- Medical Research Council [MR/L010305/1, G0500870, G9817803B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
- MRC [G0500870] Funding Source: UKRI
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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