1. Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease
- Author
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David J. Cutler, David R. Mack, Jason K. Hou, Mark S. Silverberg, Jonathan P. Bradfield, Ferdouse Begum, Michael D. Kappelman, Chengrui Huang, Michael E. Zwick, Talin Haritunians, Peter J. Mannon, Dermot P.B. McGovern, Howard A. Kader, Kim L. Isaacs, John S. Hanson, Jonathan Steven Alexander, Sharon Dudley-Brown, Dedrick E. Moulton, Jeffrey S. Hyams, Claire L. Simpson, Hakon Hakonarson, Lisa J. Herrinton, John H. Kwon, Stephan R. Targan, Mark Lazarev, Richard Kellermayer, Shehzad Ahmed Saeed, Zhenqiu Liu, Ellen Li, Lisa W. Datta, Gerald W. Dryden, John F. Kuemmerle, David T. Okou, Themistocles Dassopoulos, Subra Kugathasan, Martin Zonca, Jarod Prince, Sunny Z. Hussain, Steven R. Brant, Ashish S. Patel, Antonio Quiros, Barbara S. Kirschner, Jeffry Katz, Lee A. Denson, Tanvi Dhere, Rodney D. Newberry, Suresh Venkateswaran, Pankaj Chopra, Archana Kumar, Raymond K. Cross, Kelly A. Thomas, Bankole O. Osuntokun, Judy H. Cho, Robert N. Baldassano, Jan Micheal A. Klapproth, Richard H. Duerr, Ming-Hsi Wang, Zhi Wei, Jenifer Seminerio, John D. Rioux, and John F. Valentine
- Subjects
0301 basic medicine ,Linkage disequilibrium ,Genotyping Techniques ,Cell Adhesion Molecules, Neuronal ,Population ,Genome-wide association study ,Single-nucleotide polymorphism ,GPI-Linked Proteins ,Inflammatory bowel disease ,Polymorphism, Single Nucleotide ,HLA-DQ alpha-Chains ,White People ,Article ,03 medical and health sciences ,Crohn Disease ,Medicine ,SNP ,Humans ,KCNQ2 Potassium Channel ,Genetic Predisposition to Disease ,education ,Sorting Nexins ,Receptors, CXCR6 ,Genetics ,Crohn's disease ,education.field_of_study ,Hepatology ,business.industry ,Interleukin-12 Subunit p40 ,Gastroenterology ,Case-control study ,Tenascin ,Receptors, Interleukin ,medicine.disease ,digestive system diseases ,Black or African American ,Repressor Proteins ,030104 developmental biology ,Case-Control Studies ,Receptors, Virus ,Colitis, Ulcerative ,Receptors, Chemokine ,business ,Receptors, Prostaglandin E, EP4 Subtype ,Ubiquitin Thiolesterase ,Adenylyl Cyclases ,Genome-Wide Association Study ,HLA-DRB1 Chains - 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 −8 in meta-analysis with a nominal evidence ( P 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 −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.
- Published
- 2016