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 W. Datta; Zhi Wei; Kelly Thomas; Lisa J. Herrinton; Jan Micheal A. Klapproth; Antonio J. Quiros; Jenifer Seminerio; Zhenqiu Liu; Jonathan 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

doi:10.1053/j.gastro.2016.09.032

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 W. 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

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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 language	English (US)
Pages (from-to)	206-217.e2
Journal	Gastroenterology
Volume	152
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2016.09.032
State	Published - Jan 1 2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

Hepatology
Gastroenterology

Keywords

Genetic Analysis
Risk Factor
SNP
Trans-Ethnic

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10.1053/j.gastro.2016.09.032

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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. W., 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

@article{25b078766f194eeab4fe2232cbd4029c,

title = "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.",

keywords = "Genetic Analysis, Risk Factor, SNP, Trans-Ethnic",

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

note = "Publisher Copyright: {\textcopyright} 2017 AGA Institute",

year = "2017",

month = jan,

day = "1",

doi = "10.1053/j.gastro.2016.09.032",

language = "English (US)",

volume = "152",

pages = "206--217.e2",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "1",

}

Brant, SR, Okou, DT, Simpson, CL, Cutler, DJ, Haritunians, T, Bradfield, JP, Chopra, P, Prince, J, Begum, F, Kumar, A, Huang, C, Venkateswaran, S, Datta, LW, Wei, Z, Thomas, K, Herrinton, LJ, Klapproth, JMA, Quiros, AJ, Seminerio, J, Liu, Z, Alexander, JS, Baldassano, RN, Dudley-Brown, S, Cross, RK, Dassopoulos, T, Denson, LA, Dhere, TA, Dryden, GW, Hanson, JS, Hou, JK, Hussain, SZ, Hyams, JS, Isaacs, KL, Kader, H, Kappelman, MD, Katz, J, Kellermayer, R, Kirschner, BS, Kuemmerle, JF, Kwon, JH, Lazarev, M, Li, E, Mack, D, Mannon, P, Moulton, DE, Newberry, RD, Osuntokun, BO, Patel, AS, Saeed, SA, Targan, SR, Valentine, JF, Wang, MH, Zonca, M, Rioux, JD, Duerr, RH, Silverberg, MS, Cho, JH, Hakonarson, H, Zwick, ME, McGovern, DPB & Kugathasan, S 2017, 'Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease', Gastroenterology, vol. 152, no. 1, pp. 206-217.e2. https://doi.org/10.1053/j.gastro.2016.09.032

TY - JOUR

T1 - Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

AU - Brant, Steven R.

AU - Okou, David T.

AU - Simpson, Claire L.

AU - Cutler, David J.

AU - Haritunians, Talin

AU - Bradfield, Jonathan P.

AU - Chopra, Pankaj

AU - Prince, Jarod

AU - Begum, Ferdouse

AU - Kumar, Archana

AU - Huang, Chengrui

AU - Venkateswaran, Suresh

AU - Datta, Lisa W.

AU - Wei, Zhi

AU - Thomas, Kelly

AU - Herrinton, Lisa J.

AU - Klapproth, Jan Micheal A.

AU - Quiros, Antonio J.

AU - Seminerio, Jenifer

AU - Liu, Zhenqiu

AU - Alexander, Jonathan S.

AU - Baldassano, Robert N.

AU - Dudley-Brown, Sharon

AU - Cross, Raymond K.

AU - Dassopoulos, Themistocles

AU - Denson, Lee A.

AU - Dhere, Tanvi A.

AU - Dryden, Gerald W.

AU - Hanson, John S.

AU - Hou, Jason K.

AU - Hussain, Sunny Z.

AU - Hyams, Jeffrey S.

AU - Isaacs, Kim L.

AU - Kader, Howard

AU - Kappelman, Michael D.

AU - Katz, Jeffry

AU - Kellermayer, Richard

AU - Kirschner, Barbara S.

AU - Kuemmerle, John F.

AU - Kwon, John H.

AU - Lazarev, Mark

AU - Li, Ellen

AU - Mack, David

AU - Mannon, Peter

AU - Moulton, Dedrick E.

AU - Newberry, Rodney D.

AU - Osuntokun, Bankole O.

AU - Patel, Ashish S.

AU - Saeed, Shehzad A.

AU - Targan, Stephan R.

AU - Valentine, John F.

AU - Wang, Ming Hsi

AU - Zonca, Martin

AU - Rioux, John D.

AU - Duerr, Richard H.

AU - Silverberg, Mark S.

AU - Cho, Judy H.

AU - Hakonarson, Hakon

AU - Zwick, Michael E.

AU - McGovern, Dermot P.B.

AU - Kugathasan, Subra

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Genetic Analysis

KW - Risk Factor

KW - SNP

KW - Trans-Ethnic

UR - http://www.scopus.com/inward/record.url?scp=85006314574&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006314574&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2016.09.032

DO - 10.1053/j.gastro.2016.09.032

M3 - Article

C2 - 27693347

AN - SCOPUS:85006314574

SN - 0016-5085

VL - 152

SP - 206-217.e2

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -

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

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