Synaptic, transcriptional, and chromatin genes disrupted in autism

By Silvia De Rubeis. Nature, 2014

2,474 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/2e1a0bc381389bd753e89524d47916cb7a043ae6

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Citations in the corpus

Advancing the understanding of autism disease mechanisms through genetics (2016, neutral): “Mutations in genes encoding excitatory and inhibitory synaptic cell-adhesion molecules (including neurex-ins 43,73,74,135,136 and neuroligins 137 ), excitatory synaptic scaffolding molecules (including the SH3 and multiple ankyrin-repeat domain (SHANK) proteins 43,74,138,139 ), the excitatory…”
An expanded view of complex traits: from polygenic to omnigenic (2017, neutral): “Rare variants with larger effect sizes also contribute genetic variance (Marouli et al., 2017), especially for diseases with major fitness consequences (Simons et al., 2014) such as autism and schizophrenia (De Rubeis et al., 2014; Fromer et al., 2014; Purcell et al., 2014).”
Regional missense constraint improves variant deleteriousness prediction (2017, positive): “Taking the combined scores from 5620 cases with a neurodevelopmental disorder 1-6 and 2078 controls 10,11 , we took the top ~10% of scores and determined the fraction of those variants that came from the cases.”
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands (2017, neutral): “We compared the genes harboring damaging DNMs in our CHD cohort and in 4,778 probands with autism 30, 31 , focusing on genes in the upper quartile of brain and heart expression.”