Cystic Fibrosis Risk Variants Confer Protection Against Inflammatory Bowel Disease

Overview

Journal medRxiv

Date 2024 Dec 16

PMID 39677473

Authors

Mingrui Yu

Qian Zhang

Kai Yuan

Aleksejs Sazonovs

Christine Stevens

Laura Fachal

Carl A Anderson

Mark J Daly

Hailiang Huang

Affiliations

Soon will be listed here.

Abstract

Genetic mutations that yield defective cystic fibrosis transmembrane regulator () protein cause cystic fibrosis, a life-limiting autosomal recessive Mendelian disorder. A protective role of loss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging the largest IBD exome sequencing dataset to date, comprising 38,558 cases and 66,945 controls in the discovery stage, and 35,797 cases and 179,942 controls in the replication stage, we established a protective role of CF-risk variants against IBD based on evidence from the association test of delF508 (p-value=8.96E-11) and the gene-based burden test of CF-risk variants (p-value=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.

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