Genovese, GiulioFromer, MenachemStahl, Eli A.Ruderfer, Douglas M.Chambert, KimberlyLandén, MikaelMoran, Jennifer L.Purcell, Shaun M.Sklar, PamelaSullivan, Patrick F.Hultman, Christina M.McCarroll, Steven2017-05-012016Genovese, 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.http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630604By 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.en-USJournal Article2017-05-0110.1038/nn.4402