Background & Aims The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. Methods We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified [IBD-U]) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P<5.0×10−8 in meta-analysis with a nominal evidence (P<.05) in each scan were considered to have genome-wide significance. Results We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance associations for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P<1.6×10−6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B, PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. Conclusions We performed a genome-wide association study of African Americans with IBD and identified loci associated with CD and UC in only this population; we also replicated loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

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Background & Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the US; additional controls were collected from 4 other immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease (CD), 361 with ulcerative colitis (UC), 62 with IBD type-unknown (IBDU), and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between UC and HLA rs9271366 (P=7.5e–6), CD and 5p13.1 rs4286721 (P=3.0e–6), and IBD and KAT2A rs730086 (P=2.3e–6). Additional suggestive associations (P<4.2e-5) were observed between CD and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2 open reading frame 43; and between UC and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P<3.1e-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P<3.9e–4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2–15q23, and 16p12.2–16p12.1. Network analyses showed significant enrichment (false discovery rate <1e–5) in genes that encode members of the JAK–STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we found evidence for loci and variants not previously associated with IBD. The complex genetic factors that determine risk for or protection from IBD in different populations require further study.

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