The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability.

Nat Genet
Authors
Keywords
Abstract

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

Year of Publication
2017
Journal
Nat Genet
Volume
49
Issue
8
Pages
1167-1173
Date Published
2017 Aug
ISSN
1546-1718
DOI
10.1038/ng.3903
PubMed ID
28650482
PubMed Central ID
PMC5533219
Links
Grant list
R01 MH095034 / MH / NIMH NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
R01 CA133996 / CA / NCI NIH HHS / United States
P50 CA097007 / CA / NCI NIH HHS / United States
R01 MH077139 / MH / NIMH NIH HHS / United States
U01 MH105666 / MH / NIMH NIH HHS / United States
P01 CA089392 / CA / NCI NIH HHS / United States
R01 ES011740 / ES / NIEHS NIH HHS / United States
MR/K026992/1 / Medical Research Council / United Kingdom
MR/M008436/1 / Medical Research Council / United Kingdom
P50 DA019706 / DA / NIDA NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
R01 MH041953 / MH / NIMH NIH HHS / United States
P50 CA084724 / CA / NCI NIH HHS / United States
R01 EY020483 / EY / NEI NIH HHS / United States
100135 / Wellcome Trust / United Kingdom
R01 MH083094 / MH / NIMH NIH HHS / United States
Wellcome Trust / United Kingdom
MR/L010305/1 / Medical Research Council / United Kingdom
P50 CA093459 / CA / NCI NIH HHS / United States