Phenome-wide association study of monogenic inflammatory bowel disease genes in diverse biobanks identifies population-specific and shared Goldilocks alleles: implications for Precision Medicine.

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.

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.

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.

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.