A polygenic burden of rare disruptive mutations in schizophrenia.

Nature
Authors
Keywords
Abstract

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Year of Publication
2014
Journal
Nature
Volume
506
Issue
7487
Pages
185-90
Date Published
2014 Feb 13
ISSN
1476-4687
URL
DOI
10.1038/nature12975
PubMed ID
24463508
PubMed Central ID
PMC4136494
Links
Grant list
R01 MH095034 / MH / NIMH NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
RC2 MH089905 / MH / NIMH NIH HHS / United States
R01 MH077139 / MH / NIMH NIH HHS / United States
R01 MH091115 / MH / NIMH NIH HHS / United States
TT32MH017119 / MH / NIMH NIH HHS / United States
Medical Research Council / United Kingdom
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 MH099126 / MH / NIMH NIH HHS / United States
I01 BX002395 / BX / BLRD VA / United States
RC2MH089905 / MH / NIMH NIH HHS / United States
G0802238 / Medical Research Council / United Kingdom
T32 MH017119 / MH / NIMH NIH HHS / United States
R01 HG005827 / HG / NHGRI NIH HHS / United States
Wellcome Trust / United Kingdom
R01 MH095088 / MH / NIMH NIH HHS / United States