Exome arrays capture polygenic rare variant contributions to schizophrenia.

Hum Mol Genet
Authors
Keywords
Abstract

Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 × 10(-7)). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder.

Year of Publication
2016
Journal
Hum Mol Genet
Volume
25
Issue
5
Pages
1001-7
Date Published
2016 Mar 01
ISSN
1460-2083
URL
DOI
10.1093/hmg/ddv620
PubMed ID
26740555
PubMed Central ID
PMC4754044
Links
Grant list
MR/L010305/1 / Medical Research Council / United Kingdom
G0800509 / Medical Research Council / United Kingdom
G0801418 / Medical Research Council / United Kingdom