A polygenic burden of rare disruptive mutations in schizophrenia.
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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
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Journal | Nature
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Volume | 506
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Issue | 7487
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Pages | 185-90
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Date Published | 2014 Feb 13
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ISSN | 1476-4687
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URL | |
DOI | 10.1038/nature12975
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PubMed ID | 24463508
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PubMed Central ID | PMC4136494
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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
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