Cystic fibrosis risk variants confer protection against inflammatory bowel disease
Yu, M.; Zhang, Q.; Yuan, K.; Sazonovs, A.; Stevens, C.; Fachal, L.; the International Inflammatory Bowel Disease Genetics Consortium, ; Anderson, C.; Daly, M. J.; Huang, H.
Show abstract
Genetic mutations that yield defective cystic fibrosis transmembrane regulator (CFTR) protein cause cystic fibrosis, 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 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 CFTR 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility 96%
- Single-cell RNA sequencing reveals dysregulated cellular programmes in the inflamed epithelium of Crohn's disease patients. 94%
- Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease 93%
Similar papers in this journal
- Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases 94%
- Multiomic analysis reveals cellular and epigenetic plasticity in intestinal pouches of ulcerative colitis patients 94%
- Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33. 93%
Similar papers in this journal
- Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort 95%
- Gut microbial and human genetic signatures of inflammatory bowel disease increase risk of comorbid mental disorders 94%
- Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease 90%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.