Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
By G. Genovese, Menachem Fromer, Eli A. Stahl, D. Ruderfer, K. Chambert, M. Landén, J. Moran, Shaun Purcell, P. Sklar, Patrick F. Sullivan and 2 more. 2016
444 citations recorded by the source corpus.
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.
Subfields: Genetics
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Citations in the corpus
- Psychiatric Genomics: An Update and an Agenda (2017, background): “SETD1A is the only gene implicated to date by whole-exome sequencing studies (37), but other such studies have only found hints of biological pathways by focusing on extremely rare variation (40, 41).”
- Comparative genetic architectures of schizophrenia in East Asian and European populations (2018, unknown): “Seventy gene-sets were selected and tested in this study (Supplementary Table 8), including those from the Molecular Signatures Database 76 , related to psychiatric diseases 38,77,78 and from ‘gwaspipeline’(https://github.com/freeseek/gwaspipeline/blob/ master/makegenes.sh).”