Abstract
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.
Highlights
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets
We conducted targeted sequencing of the exons of 759 protein-coding genes in regions harbouring common variants associated to IBD10,11 in 917 healthy controls, 887 individuals with ulcerative colitis (UC) and 1,204 individuals with Crohn’s disease (CD) from the NIDDK inflammatory bowel diseases (IBDs) Genetics Consortium (North American clinical samples of European descent)
We jointly analysed these data with sequencing data from the same genes taken from an exome-sequencing data set of Finnish individuals: 508 with UC; 238 with CD; and 8,124 Finnish reference samples sequenced within Sequencing Initiative Suomi (SISu) project[12]
Summary
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. 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 total of 200 loci have been unequivocally implicated in the two common forms of inflammatory bowel diseases (IBDs): Crohn’s disease (CD) and ulcerative colitis (UC)[1,2] For these findings, like most genome-wide association study (GWAS) results, it has proven challenging to infer the functional consequences of common variant associations[3] beyond cases where protein-altering variants have been directly implicated. We conduct targeted sequencing of the exons of 759 protein-coding genes in regions harbouring common variants associated to IBD in 917 healthy controls, 887 individuals with UC (cases) and 1,204 individuals with CD (cases) to identify predicted PTVs that may confer protection to disease. By combining RNA allele-specific expression, protein expression and immunoflourescene imaging, we find 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
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