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.