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

Giulio Genovese, Menachem Fromer, Eli A. Stahl, Douglas M. Ruderfer, Kimberly Chambert, Mikael Landén, Jennifer L. Moran, Shaun M. Purcell, Pamela Sklar, Patrick F. Sullivan, Christina M. Hultman, Steven A. McCarroll

Research output: Contribution to journalArticlepeer-review

266 Scopus citations


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.

Original languageEnglish
Pages (from-to)1433-1441
Number of pages9
JournalNature Neuroscience
Issue number11
StatePublished - 26 Oct 2016


Dive into the research topics of 'Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia'. Together they form a unique fingerprint.

Cite this