Steven R Brant1, David T Okou2, Claire L Simpson3, David J Cutler4, Talin Haritunians5, Jonathan P Bradfield6, Pankaj Chopra4, Jarod Prince2, Ferdouse Begum7, Archana Kumar2, Chengrui Huang7, Suresh Venkateswaran2, Lisa W Datta8, Zhi Wei6, Kelly Thomas6, Lisa J Herrinton9, Jan-Micheal A Klapproth10, Antonio J Quiros11, Jenifer Seminerio12, Zhenqiu Liu5, Jonathan S Alexander13, Robert N Baldassano14, Sharon Dudley-Brown15, Raymond K Cross16, Themistocles Dassopoulos17, Lee A Denson18, Tanvi A Dhere19, Gerald W Dryden20, John S Hanson21, Jason K Hou22, Sunny Z Hussain23, Jeffrey S Hyams24, Kim L Isaacs25, Howard Kader26, Michael D Kappelman27, Jeffry Katz28, Richard Kellermayer29, Barbara S Kirschner30, John F Kuemmerle31, John H Kwon32, Mark Lazarev33, Ellen Li34, David Mack35, Peter Mannon36, Dedrick E Moulton37, Rodney D Newberry38, Bankole O Osuntokun39, Ashish S Patel40, Shehzad A Saeed18, Stephan R Targan5, John F Valentine41, Ming-Hsi Wang42, Martin Zonca43, John D Rioux44, Richard H Duerr45, Mark S Silverberg46, Judy H Cho47, Hakon Hakonarson6, Michael E Zwick4, Dermot P B McGovern5, Subra Kugathasan48. 1. Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 2. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia. 3. Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee; Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland. 4. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia. 5. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. 6. Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 7. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 8. Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. 9. Kaiser Permanente, Oakland, California. 10. University of Pennsylvania, Philadelphia, Pennsylvania. 11. Department of Pediatrics, Medical University of South Carolina, Pediatric Center for Inflammatory Bowel Disorders, Summerville, South Carolina. 12. Department of Gastroenterology, Medical University of South Carolina Digestive Disease Center, Charleston, South Carolina. 13. Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana. 14. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 15. Department of Medicine, Johns Hopkins University Schools of Medicine & Nursing, Baltimore, Maryland. 16. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. 17. Department of Medicine, Washington University School of Medicine, St Louis, Missouri. 18. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 19. Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. 20. Department of Medicine, University of Louisville, Louisville, Kentucky. 21. Charlotte Gastroenterology and Hepatology, Charlotte, North Carolina. 22. Department of Medicine, Baylor College of Medicine; Veterans Affairs Health Services Research and Development Service, Center for Innovations in Quality Effectiveness and Safety; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. 23. Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, Louisiana. 24. Connecticut Children's Medical Center, Hartford, Connecticut. 25. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 26. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland. 27. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 28. Case Western Reserve University, Cleveland, Ohio. 29. Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas. 30. Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, Illinois. 31. Medicine and Physiology and Biophysics, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia. 32. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. 33. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 34. Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York. 35. Department of Pediatrics, University of Ottawa and Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. 36. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. 37. Vanderbilt Children's Hospital, Nashville, Tennessee. 38. Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri. 39. Department of Pediatrics, Cook Children's Medical Center, Fort Worth, Texas. 40. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. 41. University of Utah, Health Sciences, Salt Lake City, Utah. 42. Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, Florida. 43. Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan. 44. Department of Medicine, Université de Montréal and the Montreal Heart Institute Research Center, Montreal, Quebec, Canada. 45. Department of Medicine and Clinical and Translational Science Institute, School of Medicine and Department of Human Genetics, Graduate School of Public Health; University of Pittsburgh, Pittsburgh, Pennsylvania. 46. Department of Medicine, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Toronto, Ontario, Canada. 47. Medicine and Genetics, Icahn School of Medicine at Mount Sinai, Charles Bronfman Institute for Personalized Medicine, New York, New York. 48. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia. Electronic address: skugath@emory.edu.
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.
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.
Authors: Chengrui Huang; Talin Haritunians; David T Okou; Dermot P B McGovern; Steven R Brant; Subra Kugathasan; David J Cutler; Michael E Zwick; Kent D Taylor; Lisa W Datta; Joseph C Maranville; Zhenqiu Liu; Shannon Ellis; Pankaj Chopra; Jonathan S Alexander; Robert N Baldassano; Raymond K Cross; Themistocles Dassopoulos; Tanvi A Dhere; Richard H Duerr; John S Hanson; Jason K Hou; Sunny Z Hussain; Kim L Isaacs; Kelly E Kachelries; Howard Kader; Michael D Kappelman; Jeffrey Katz; Richard Kellermayer; Barbara S Kirschner; John F Kuemmerle; Archana Kumar; John H Kwon; Mark Lazarev; Peter Mannon; Dedrick E Moulton; Bankole O Osuntokun; Ashish Patel; John D Rioux; Jerome I Rotter; Shehzad Saeed; Ellen J Scherl; Mark S Silverberg; Ann Silverman; Stephan R Targan; John F Valentine; Ming-Hsi Wang; Claire L Simpson; S Louis Bridges; Robert P Kimberly; Stephen S Rich; Judy H Cho; Anna Di Rienzo; Linda W H Kao Journal: Gastroenterology Date: 2015-08-14 Impact factor: 22.682
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Michael D Kappelman; Sheryl L Rifas-Shiman; Carol Q Porter; Daniel A Ollendorf; Robert S Sandler; Joseph A Galanko; Jonathan A Finkelstein Journal: Gastroenterology Date: 2008-09-17 Impact factor: 22.682
Authors: David J Cutler; Michael E Zwick; David T Okou; Sampath Prahalad; Thomas Walters; Stephen L Guthery; Marla Dubinsky; Robert Baldassano; Wallace V Crandall; Joel Rosh; James Markowitz; Michael Stephens; Richard Kellermayer; Marian Pfefferkorn; Melvin B Heyman; Neal LeLeiko; David Mack; Dedrick Moulton; Michael D Kappelman; Archana Kumar; Jarod Prince; Promita Bose; Kajari Mondal; Dhanya Ramachandran; John F Bohnsack; Anne M Griffiths; Yael Haberman; Jonah Essers; Susan D Thompson; Bruce Aronow; David J Keljo; Jeffrey S Hyams; Lee A Denson; Subra Kugathasan Journal: PLoS One Date: 2015-06-22 Impact factor: 3.240
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