Douglas M Ruderfer | Search bioRxiv

bioRxiv2016

The ExAC Browser: Displaying reference data information from over 60,000 exomes

Worldwide, hundreds of thousands of humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation and understanding gene function. Here, we present a lightweight, flexible browser framework to display large population datasets of genetic variation. We demonstrate its use for exome sequence data from 60,706 individuals in the Exome Aggregation Consortium (ExAC). The ExAC browser provides gene- and transcript-centric displays of variation, a critical view for clinical applications. Additionally, we provide a variant display, which includes population frequency and functional annotation data as well as short read support for the called variant. This browser is open-source, freely available, and has already been used extensively by clinical laboratories worldwide.

Genomics↗

bioRxiv2016

Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

Over 100 genetic loci harbor schizophrenia associated variants, yet how these common variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating the largest publicly available resource to date of gene expression and its genetic regulation; [~]5 times larger than the latest release of GTEx. Using this resource, we find that [~]20% of the schizophrenia risk loci have common variants that could explain regulation of brain gene expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of FURIN1 in neural progenitor cells derived from human induced pluripotent stem cells produces abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential expression between cases and controls, 44% show some evidence for differential expression. All fold changes are [≤] 1.33, and an independent cohort yields similar differential expression for these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly polygenic, as has been reported in investigations of common and rare genetic variation. Co-expression analyses identify a gene module that shows enrichment for genetic associations and is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic interpretations of genetic liability for schizophrenia and other brain diseases.

Genomics↗