Systematic reconstruction of autism biology from massive genetic mutation profiles.

TitleSystematic reconstruction of autism biology from massive genetic mutation profiles.
Publication TypeJournal Article
Year of Publication2018
AuthorsLuo W, Zhang C, Jiang Y-H, Brouwer CR
JournalSci Adv
Date Published2018 04

<p>Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3',5'-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein-coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity.</p>

Alternate JournalSci Adv
PubMed ID29651456
PubMed Central IDPMC5895441
Grant ListR01 NS089676 / NS / NINDS NIH HHS / United States
R21 HD087795 / HD / NICHD NIH HHS / United States
R21 MH104316 / MH / NIMH NIH HHS / United States
R01 MH098114 / MH / NIMH NIH HHS / United States
R01 GM124486 / GM / NIGMS NIH HHS / United States