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 × 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.
Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
G. Genovese,M. Fromer,E. Stahl,D. Ruderfer,K. Chambert,M. Landén,J. Moran,S. Purcell,P. Sklar,P. Sullivan,C. Hultman,S. Mccarroll
Published 2016 in Nature Neuroscience
ABSTRACT
PUBLICATION RECORD
- Publication year
2016
- Venue
Nature Neuroscience
- Publication date
2016-09-09
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
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