Cystic fibrosis risk variants confer protection against inflammatory bowel disease

TL;DR

Cystic fibrosis risk variants are found to protect against inflammatory bowel disease, suggesting a potential new therapeutic approach.

Contribution

Demonstrates a protective role of cystic fibrosis risk variants against IBD using large-scale sequencing data.

Findings

CF-risk variants are associated with reduced IBD susceptibility (p = 8.96E−11 for deltaF508).

Clinical annotations outperform in silico methods like AlphaMissense in variant prioritization.

The study emphasizes the need for better variant prioritization in gene-based burden tests.

Abstract

Genetic mutations that yield a defective cystic fibrosis (CF) transmembrane regulator (CFTR) protein cause CF, a life-limiting autosomal-recessive Mendelian disorder. A protective role of CFTR loss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging a large IBD exome sequencing dataset comprising 38,558 cases and 66,945 controls of European ancestry in the discovery stage and a combined total of 42,475 cases and 192,050 controls across diverse ancestry groups in the replication stage, we established a protective role of CF-risk variants against IBD based on the association test of CFTR deltaF508 (p = 8.96E−11) and the gene-based burden test of CF-risk variants (p = 3.9E−07). Furthermore, we assessed variant prioritization methods, including AlphaMissense, using clinically annotated CF-risk variants as the gold standard. Our findings highlight the critical and unmet need for effective variant prioritization in gene-based burden tests.

•Large-scale sequencing study of inflammatory bowel disease (IBD)•Genetic mutations known to cause cystic fibrosis are protective against IBD•Accurate variant functional annotation enhances the power of rare-variant burden tests•In silico variant annotations (e.g., AlphaMissense) underperform clinical annotations

Large-scale sequencing study of inflammatory bowel disease (IBD)

Genetic mutations known to cause cystic fibrosis are protective against IBD

Accurate variant functional annotation enhances the power of rare-variant burden tests

In silico variant annotations (e.g., AlphaMissense) underperform clinical annotations

Through large-scale sequencing analysis, Yu et al. found that cystic fibrosis risk variants reduce susceptibility to IBD. This finding opens the possibility of developing selective, tissue-targeted CFTR modulators as a novel IBD therapeutic intervention. Their analysis also highlights the critical and unmet need for effective variant prioritization in gene-based burden tests.

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