Exome analyses reveal new autism genes in synaptic, transcriptional, and chromatin networks. S. De Rubeis1,2, K. Roeder3,4, B. Devlin5, M. J. Daly6,7,8, J. D. Buxbaum1,2,9,10,11,12, The Autism Sequencing Consortium 1) Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 2) Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 3) Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA; 4) Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA; 5) Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 6) The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; 7) Harvard Medical School, Boston, Massachusetts, USA; 8) Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; 9) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 10) Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 11) Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 12) The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

   The genetic architecture of autism spectrum disorder involves the interplay of common and rare variation and their impact on hundreds of genes. During the past two years, large-scale whole-exome sequencing (WES) has proved fruitful in uncovering risk-conferring variation, especially when considering de novo variation, which is sufficiently rare that recurrent de novo mutations in a gene provide strong causal evidence. Here, we conduct the largest ASD WES study to date, starting with 16,098 samples from seventeen distinct sample sources and ascertained by diverse designs. Unlike earlier WES studies, we do not rely solely on counting de novo loss-of-function (LoF) variants, rather we use novel statistical methods (Xin He for the Autism Sequencing Consortium) to assess association for autosomal genes by integrating de novo, inherited and case-control LoF counts, as well as de novo missense variants predicted to be damaging. Analyses of sequence data in a cleaned sample of 3,871 autism cases and 9,937 ancestry-matched or parent controls implicate 22 autosomal genes at a false discovery rate (FDR) < 0.05, and a much broader set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes show unusual evolutionary constraint against mutations and map to modules in unbiased networks of early neocortical developmental. Our dataset is enriched with genes targeted by two autism-associated RNA-binding proteins (FMRP and RBFOX), genes found with de novo non-synonymous mutations in schizophrenia, and genes encoding synaptic components. Amongst critical synaptic genes found mutated in our study are voltage-gated ion channels, including those involved in propagation of action potentials (e.g., the Na+ channel Nav1.2 encoded by SCN2A), neuronal pacemaking, and excitability-transcription coupling (e.g., the Ca2+ channel Cav1.3 encoded by CACNA1D). Our dataset is also enriched for chromatin remodeling genes, including enzymes involved in histone post-translational modifications, especially lysine methylation/demethylation, and regulators that recognize such marks and alter chromatin plasticity such as the emergent ASD gene CHD8. In conclusion, our study identifies a group of 107 high-confidence risk genes that incur de novo LoF mutations in over 5% of ASD subjects and expose two tightly intertwined pathways - chromatin remodeling and synaptic development - as major themes in ASD risk.

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