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Protein-truncating variants protective against human disease provide  in vivo  validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in  RNF186 , a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall  P =6.89 × 10 −7 , odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis