Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.

Nat Genet
Authors
Keywords
Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
3
Pages
381-389
Date Published
2018 03
ISSN
1546-1718
DOI
10.1038/s41588-018-0059-2
PubMed ID
29483656
PubMed Central ID
PMC5918692
Links
Grant list
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
R01 AA007535 / AA / NIAAA NIH HHS / United States
R01 AA014041 / AA / NIAAA NIH HHS / United States
R01 MH066206 / MH / NIMH NIH HHS / United States
R01 MH110927 / MH / NIMH NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
R01 AA013321 / AA / NIAAA NIH HHS / United States
MR/P005748/1 / MRC_ / Medical Research Council / United Kingdom
G19/2 / MRC_ / Medical Research Council / United Kingdom
MR/L011794/1 / MRC_ / Medical Research Council / United Kingdom
R01 DA012854 / DA / NIDA NIH HHS / United States
K99 MH113823 / MH / NIMH NIH HHS / United States
WT_ / Wellcome Trust / United Kingdom
R01 AA013320 / AA / NIAAA NIH HHS / United States
R01 AA013326 / AA / NIAAA NIH HHS / United States
R01 HD059215 / HD / NICHD NIH HHS / United States
R56 DA012854 / DA / NIDA NIH HHS / United States
R01 HD044454 / HD / NICHD NIH HHS / United States
K08 DA019951 / DA / NIDA NIH HHS / United States
MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom