| Title: | Phenome-wide association study of monogenic inflammatory bowel disease genes in diverse biobanks identifies population-specific and shared Goldilocks alleles: implications for Precision Medicine |
| Journal: | Journal of Crohn's and Colitis |
| Published: | 3 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40802484/ |
| DOI: | https://doi.org/10.1093/ecco-jcc/jjaf098 |
Publication 16331
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Abstract
BACKGROUND AND AIMS: Monogenic forms of inflammatory bowel disease (IBD) are driven by variants in genes critical to pathways in intestinal homeostasis and immunity. We investigated gene- and variant-level effects of these genes with IBD and phenome-wide association, leveraging large-scale whole exome sequencing data across 4 diverse cohorts: BioMe Biobank (Regeneron and Sema4), Penn Med Biobank, and UK Biobank.</p>
METHODS: Predicted loss- and gain-of function variants were extracted from 102 monogenic genes. Gene- and variant-level association tests for binary traits were performed across 4 cohorts grouped based on genetic similarity in European, African, and Admixed American populations.</p>
RESULTS: From 11 546 variants extracted, over two-thirds were predicted as loss-of-function (LOF), with 93% classified as ultra-rare and 1172 Goldilocks variants (not ultra-rare) enriched at least 10-fold in African populations. Gene-level IBD association testing demonstrated numerous replicated associations in European cohorts, reflecting well-powered independent cohorts. Twenty monogenic genes overlap with genome-wide IBD loci, fifteen of which displayed gene-level association trends. Heterozygous carriage of African-predominant LOF alleles in NPC1 (intracellular cholesterol transport) and ADA/ADA2 (purine metabolism), were associated with IBD. These variants also showed replicated associations with phenotypes related to cardiac conduction, infection, and lipid metabolism.</p>
CONCLUSIONS: We define overlap between monogenic and genome-wide IBD loci and reveal population-specific allelic heterogeneity of IBD risk genes. We uncover novel phenotype associations suggesting pleiotropic effects of monogenic IBD genes. African-predominant variants revealed allelic associations absent in European cohorts, and of potential clinical significance, underscoring the importance of increasing diversity in genetic studies.</p>
8 Authors
- Michelle M Bao
- Meltem Ece Kars
- David Zhang
- Kyle Gettler
- Daniel Rader
- Scott Snapper
- Yuval Itan
- Judy H Cho
1 Application
| Application ID | Title |
|---|---|
| 53074 | Identifying novel high-impact rare disease-causing mutations, genes and pathways in inflammatory bowel disease patients |
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