Genomic Insights Into Inflammatory Bowel Disease in United States Hispanic Participants: An Ancestry-Focused Study.

Genetic admixture of United States Hispanic individuals provides a unique opportunity to examine ancestral origins of inflammatory bowel disease (IBD) risk. In ∼7.3K Hispanic participants (1660 IBD cases; 5614 controls), we examined ancestral heterogeneity of IBD clinical phenotypes and sought to identify IBD risk loci that displayed heterogeneity of effect or were ancestry-specific. Association of genetic ancestry with clinical phenotypes was evaluated. We conducted an ancestry-informed genome-wide (GW) association study for IBD, ulcerative colitis, and Crohn's disease (CD) to obtain ancestry-specific effect size estimates for alleles from African (AFR), European (EUR), and Amerindian (AIAN) origin. Ancestry-specific replication was assessed in All of Us Hispanic participants and transferability was evaluated for populations with similar ancestral origin. Clinical phenotypes were associated with higher AFR (colonic, penetrating, or perianal CD; later age at diagnosis; IBD-related surgery) or AIAN ancestry (colonic CD). GW EUR-specific associations were observed within established loci for CD (NOD2, IL23R, HLA-DRA) and ulcerative colitis (HLA locus). For AFR or AIAN alleles, novel GW associations were observed in 14 loci. One AFR-specific IBD GW (PCGEM1) and 2 AFR-specific suggestive (TYROBP/LRFN3) associations replicated in All of Us. Several suggestive associations demonstrated transferability (AFR-specific TYROBP/LRFN3 and AIAN-specific GAD2). Several novel IBD risk variants also demonstrated association with clinical phenotypes. Ancestry-informed regression enabled identification of novel AFR and AIAN-specific risk alleles, which may also inform observed phenotypic differences. We have shown that some previously identified IBD loci have associations that are EUR-specific. These findings highlight the importance of genetic ancestry for elucidating the biological underpinnings of IBD and may have important pharmacogenetic implications.