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

Steven R. Brant, David T. Okou, Claire L. Simpson, David J. Cutler, Talin Haritunians, Jonathan P. Bradfield, Pankaj Chopra, Jarod Prince, Ferdouse Begum, Archana Kumar, Chengrui Huang, Suresh Venkateswaran, Lisa Datta, Zhi Wei, Kelly Thomas, Lisa J. Herrinton, Jan Micheal A Klapproth, Antonio J. Quiros, Jenifer Seminerio, Zhenqiu LiuJonathan S. Alexander, Robert N. Baldassano, Sharon Dudley-Brown, Raymond K. Cross, Themistocles Dassopoulos, Lee A. Denson, Tanvi A. Dhere, Gerald W. Dryden, John S. Hanson, Jason K. Hou, Sunny Z. Hussain, Jeffrey S. Hyams, Kim L. Isaacs, Howard Kader, Michael D. Kappelman, Jeffry Katz, Richard Kellermayer, Barbara S. Kirschner, John F. Kuemmerle, John H. Kwon, Mark Lazarev, Ellen Li, David Mack, Peter Mannon, Dedrick E. Moulton, Rodney D. Newberry, Bankole O. Osuntokun, Ashish S. Patel, Shehzad A. Saeed, Stephan R. Targan, John F. Valentine, Ming Hsi Wang, Martin Zonca, John D. Rioux, Richard H. Duerr, Mark S. Silverberg, Judy H. Cho, Hakon Hakonarson, Michael E. Zwick, Dermot P B McGovern, Subra Kugathasan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)206-217.e2
JournalGastroenterology
Volume152
Issue number1
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Genetic Analysis
  • Risk Factor
  • SNP
  • Trans-Ethnic

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Brant, S. R., Okou, D. T., Simpson, C. L., Cutler, D. J., Haritunians, T., Bradfield, J. P., Chopra, P., Prince, J., Begum, F., Kumar, A., Huang, C., Venkateswaran, S., Datta, L., Wei, Z., Thomas, K., Herrinton, L. J., Klapproth, J. M. A., Quiros, A. J., Seminerio, J., ... Kugathasan, S. (2017). Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology, 152(1), 206-217.e2. https://doi.org/10.1053/j.gastro.2016.09.032