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Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

ABSTRACT: 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) 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 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 UC in only this population; we also replicated IBD, CD, and UC 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.

SUBMITTER: Brant SR

PROVIDER: S-EPMC5164948 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

Brant Steven R SR Okou David T DT Simpson Claire L CL Cutler David J DJ Haritunians Talin T Bradfield Jonathan P JP Chopra Pankaj P Prince Jarod J Begum Ferdouse F Kumar Archana A Huang Chengrui C Venkateswaran Suresh S Datta Lisa W LW Wei Zhi Z Thomas Kelly K Herrinton Lisa J LJ Klapproth Jan-Micheal A JA Quiros Antonio J AJ Seminerio Jenifer J Liu Zhenqiu Z Alexander Jonathan S JS Baldassano Robert N RN Dudley-Brown Sharon S Cross Raymond K RK Dassopoulos Themistocles T Denson Lee A LA Dhere Tanvi A TA Dryden Gerald W GW Hanson John S JS Hou Jason K JK Hussain Sunny Z SZ Hyams Jeffrey S JS Isaacs Kim L KL Kader Howard H Kappelman Michael D MD Katz Jeffry J Kellermayer Richard R Kirschner Barbara S BS Kuemmerle John F JF Kwon John H JH Lazarev Mark M Li Ellen E Mack David D Mannon Peter P Moulton Dedrick E DE Newberry Rodney D RD Osuntokun Bankole O BO Patel Ashish S AS Saeed Shehzad A SA Targan Stephan R SR Valentine John F JF Wang Ming-Hsi MH Zonca Martin M Rioux John D JD Duerr Richard H RH Silverberg Mark S MS Cho Judy H JH Hakonarson Hakon H Zwick Michael E ME McGovern Dermot P B DP Kugathasan Subra S

Gastroenterology 20160928 1

<h4>Background & aims</h4>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.<h4>Methods</h4>We performed 2 high-density, genome-wide scans comprising 2345 cases of African American ...[more]

PMID: 27693347

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Project description:Background & aimsInflammatory 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.MethodsWe recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed.ResultsThe strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis 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 < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-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 <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles.ConclusionsIn 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 also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Dataset Information

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

Publications

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

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