NATURE | ARTICLE

Synaptic, transcriptional and chromatin genes disrupted in autism

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13772.html 

Nature(2014) doi:10.1038/nature13772 Received 18 May 2014 Accepted 18 August 2014 Published online 29 October 2014

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.

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Conclusion

Complementing earlier reports, ASD subjects show a clear excess of de novo LoF mutations above expectation, with a concentration of such events in a handful of genes. While this handful has a large effect on risk, most ASD genes have a much smaller impact. This gradient emerges most notably from the contrast of risk variation in male and female ASD subjects. Unlike some earlier studies, but consistent with expectation, the data also show clear evidence for effect of de novo missense SNVs on risk; for risk generated by LoF variants transmitted from unaffected parents; and for the value of case-control design in gene discovery. By integrating data on de novo, inherited and case-control variation, the yield of ASD gene discoveries was doubled over what would be obtained from a count of de novo LoF variants alone. ASD genes almost uniformly show strong constraints against variation, a feature we exploit to implicate other genes in risk.

Three critical pathways for typical development are damaged by risk variation: chromatin remodelling, transcription and splicing, and synaptic function. Chromatin remodelling controls events underlying the formation of neural connections, including neurogenesis and neural differentiation⁴⁴, and relies on epigenetic marks as post-translational modifications of histones . Here we provide extensive evidence for HMGs and readers in sporadic ASD, implicating specifically lysine methylation and extending the mutational landscape of the emergent ASD gene CHD8 to missense variants. Splicing is implicated by the enrichment of RBFOX targets in the top ASD candidates. Risk variation also affects multiple classes and components of synaptic networks, from receptors and ion channels to scaffolding proteins. Because a wide set of synaptic genes is disrupted in idiopathic ASD, it seems reasonable to suggest that altered chromatin dynamics and transcription, induced by disruption of relevant genes, leads to impaired synaptic function as well. De novo mutations in ASD^{11, 12, 13, 14,15}, intellectual disability⁴⁵ and schizophrenia³⁰ cluster to synaptic genes, and synaptic defects have been reported in models of these disorders⁴⁶. Integrity of synaptic function is essential for neural physiology, and its perturbation could represent the intersection between diverse neuropsychiatric disorders⁴⁷.