Journal
NATURE NEUROSCIENCE
Volume 19, Issue 11, Pages 1433-1441Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4402
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Funding
- National Human Genome Research Institute [U54 HG003067, R01 HG006855]
- National Institute of Mental Health [R01 MH077139, R01 MH095034, RC2 MH089905]
- Stanley Center for Psychiatric Research
- Alexander and Margaret Stewart Trust
- Sylvan C. Herman Foundation
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By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 x 10(-10)). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
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