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Published on: February 27, 2014
Genomic Insights Into Inflammatory Bowel Disease in United States Hispanic Participants: An Ancestry-Focused Study
Ashley H Beecham1, Dermot P B McGovern2, Steven W Brugger3
1Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston Salem, North Carolina; John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, Florida.
Background & Aims:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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