Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

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Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

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Title: Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
Author: Genovese, Giulio; Fromer, Menachem; Stahl, Eli A.; Ruderfer, Douglas M.; Chambert, Kimberly; Landén, Mikael; Moran, Jennifer L.; Purcell, Shaun M.; Sklar, Pamela; Sullivan, Patrick F.; Hultman, Christina M.; McCarroll, Steven A.

Note: Order does not necessarily reflect citation order of authors.

Citation: Genovese, G., M. Fromer, E. A. Stahl, D. M. Ruderfer, K. Chambert, M. Landén, J. L. Moran, et al. 2016. “Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.” Nature neuroscience 19 (11): 1433-1441. doi:10.1038/nn.4402. http://dx.doi.org/10.1038/nn.4402.
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Abstract: By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 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 in schizophrenia cases than 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 genetic signal 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.
Published Version: doi:10.1038/nn.4402
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104192/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630604
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