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



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 × 10-8in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance.



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.



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.
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.
Steven R
SR
Brant
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
David T
DT
Okou
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.
Claire L
CL
Simpson
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
David J
DJ
Cutler
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Talin
T
Haritunians
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Jonathan P
JP
Bradfield
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
Pankaj
P
Chopra
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
Jarod
J
Prince
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Ferdouse
F
Begum
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
Archana
A
Kumar
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Chengrui
C
Huang
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
Suresh
S
Venkateswaran
Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Lisa W
LW
Datta
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Zhi
Z
Wei
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Kelly
K
Thomas
Kaiser Permanente, Oakland, California.
Lisa J
LJ
Herrinton
University of Pennsylvania, Philadelphia, Pennsylvania.
Jan-Micheal A
JA
Klapproth
Department of Pediatrics, Medical University of South Carolina, Pediatric Center for Inflammatory Bowel Disorders, Summerville, South Carolina.
Antonio J
AJ
Quiros
Department of Gastroenterology, Medical University of South Carolina Digestive Disease Center, Charleston, South Carolina.
Jenifer
J
Seminerio
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Zhenqiu
Z
Liu
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
Jonathan S
JS
Alexander
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Robert N
RN
Baldassano
Department of Medicine, Johns Hopkins University Schools of Medicine & Nursing, Baltimore, Maryland.
Sharon
S
Dudley-Brown
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
Raymond K
RK
Cross
Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
Themistocles
T
Dassopoulos
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Lee A
LA
Denson
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
Tanvi A
TA
Dhere
Department of Medicine, University of Louisville, Louisville, Kentucky.
Gerald W
GW
Dryden
Charlotte Gastroenterology and Hepatology, Charlotte, North Carolina.
John S
JS
Hanson
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.
Jason K
JK
Hou
Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, Louisiana.
Sunny Z
SZ
Hussain
Connecticut Children's Medical Center, Hartford, Connecticut.
Jeffrey S
JS
Hyams
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Kim L
KL
Isaacs
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland.
Howard
H
Kader
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Michael D
MD
Kappelman
Case Western Reserve University, Cleveland, Ohio.
Jeffry
J
Katz
Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.
Richard
R
Kellermayer
Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, Illinois.
Barbara S
BS
Kirschner
Medicine and Physiology and Biophysics, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia.
John F
JF
Kuemmerle
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
John H
JH
Kwon
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Mark
M
Lazarev
Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York.
Ellen
E
Li
Department of Pediatrics, University of Ottawa and Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
David
D
Mack
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Peter
P
Mannon
Vanderbilt Children's Hospital, Nashville, Tennessee.
Dedrick E
DE
Moulton
Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri.
Rodney D
RD
Newberry
Department of Pediatrics, Cook Children's Medical Center, Fort Worth, Texas.
Bankole O
BO
Osuntokun
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
Ashish S
AS
Patel
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Shehzad A
SA
Saeed
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Stephan R
SR
Targan
University of Utah, Health Sciences, Salt Lake City, Utah.
John F
JF
Valentine
Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, Florida.
Ming-Hsi
MH
Wang
Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan.
Martin
M
Zonca
Department of Medicine, Université de Montréal and the Montreal Heart Institute Research Center, Montreal, Quebec, Canada.
John D
JD
Rioux
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.
Richard H
RH
Duerr
Department of Medicine, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Toronto, Ontario, Canada.
Mark S
MS
Silverberg
Medicine and Genetics, Icahn School of Medicine at Mount Sinai, Charles Bronfman Institute for Personalized Medicine, New York, New York.
Judy H
JH
Cho
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Hakon
H
Hakonarson
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
Michael E
ME
Zwick
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Dermot P B
DP
McGovern
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.
Subra
S
Kugathasan
D000262:Adenylyl Cyclases / Q000235:genetics; D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D059848:HLA-DQ alpha-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D051658:KCNQ2 Potassium Channel / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics; D011991:Receptors, Virus / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D058305:Sorting Nexins / Q000235:genetics; D019063:Tenascin / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D044465:White People / Q000235:genetics
C106330:CXCR6 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D059811:HLA-DRB1 Chains; C500879:IL12B protein, human; C515500:IL23R protein, human; D053762:Interleukin-12 Subunit p40; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; C545650:PTGER4 protein, human; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011991:Receptors, Virus; D012097:Repressor Proteins; C528103:SNX20 protein, human; D058305:Sorting Nexins; D019063:Tenascin; C404488:USP25 protein, human; C502775:ZNF649 protein, human; C095362:limbic system-associated membrane protein; D043222:Ubiquitin Thiolesterase; D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3
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