Synaptic, transcriptional, and chromatin genes disrupted in autism

By Silvia de Rubeis, Xin He, A. Goldberg, Christopher S. Poultney, Kaitlin E. Samocha, A. Cicek, Y. Kou, Li Liu, Menachem Fromer, S. Walker and 81 more. Nature, 2014

816 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/8dd20df4dc3fc9bf95dcb5948cb2d95c09145ec2

Citations in the corpus

• Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci (2015, neutral): “In combination with exome analyses of additional large ASD cohorts (De Rubeis et al., 2014; Liu et al., 2013; Neale et al., 2012), these frameworks have dramatically accelerated gene discovery in ASD.”
• 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).”