Genome-wide association identifies multiple ulcerative colitis susceptibility loci

被引：538

作者：

McGovern, Dermot P. B. ^{[1
]}

Gardet, Agnes ^{[2
,3
]}

Torkvist, Leif ^{[4
,5
]}

Goyette, Philippe ^{[6
,7
]}

Essers, Jonah ^{[8
]}

Taylor, Kent D. ^{[9
]}

Neale, Benjamin M. ^{[8
]}

Ong, Rick T. H. ^{[10
]}

Lagace, Caroline ^{[6
,7
]}

Li, Chun ^{[2
,3
]}

Green, Todd ^{[11
]}

Stevens, Christine R. ^{[11
]}

Beauchamp, Claudine ^{[6
,7
]}

Fleshner, Phillip R. ^{[1
]}

Carlson, Marie ^{[12
]}

D'Amato, Mauro ^{[13
]}

Halfvarson, Jonas ^{[14
]}

Hibberd, Martin L. ^{[15
]}

Lordal, Mikael ^{[5
,16
]}

Padyukov, Leonid ^{[17
]}

Andriulli, Angelo ^{[18
]}

Colombo, Elisabetta ^{[18
]}

Latiano, Anna ^{[18
]}

Palmieri, Orazio ^{[18
]}

Bernard, Edmond-Jean ^{[19
]}

Deslandres, Colette ^{[20
]}

Hommes, Daan W. ^{[21
]}

de Jong, Dirk J. ^{[22
]}

Stokkers, Pieter C. ^{[23
]}

Weersma, Rinse K. ^{[24
]}

Sharma, Yashoda ^{[26
]}

Silverberg, Mark S. ^{[27
]}

Cho, Judy H. ^{[26
,28
]}

Wu, Jing ^{[29
]}

Roeder, Kathryn ^{[30
,31
]}

Brant, Steven R. ^{[30
,31
]}

Schumm, L. Phillip ^{[32
]}

Duerr, Richard H. ^{[33
,34
]}

Dubinsky, Marla C. ^{[1
]}

Glazer, Nicole L. ^{[35
,36
]}

Haritunians, Talin ^{[9
]}

Ippoliti, Andy ^{[1
]}

Melmed, Gil Y. ^{[1
]}

Siscovick, David S. ^{[35
,36
]}

Vasiliauskas, Eric A. ^{[1
]}

Targan, Stephan R. ^{[1
]}

Annese, Vito ^{[18
]}

Wijmenga, Cisca ^{[37
]}

Pettersson, Sven ^{[38
,39
]}

Rotter, Jerome I. ^{[9
]}

机构：

[1] Cedars Sinai Med Ctr, Inflammatory Bowel & Immunobiol Res Inst, Los Angeles, CA 90048 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA

[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastroenterol Unit, Boston, MA USA

[4] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden

[5] Karolinska Univ Hosp, IBD Clin Res Grp, Stockholm, Sweden

[6] Univ Montreal, Montreal, PQ, Canada

[7] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada

[8] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA

[9] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[10] Genome Inst Singapore, Singapore, Singapore

[11] MIT & Harvard, Broad Inst, Cambridge, MA USA

[12] Univ Uppsala Hosp, Dept Med Sci, Gastroenterol Res Grp, Uppsala, Sweden

[13] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden

[14] Orebro Univ Hosp, Dept Internal Med, Div Gastroenterol, Orebro, Sweden

[15] Genome Inst Singapore, Singapore, Singapore

[16] Karolinska Univ Hosp, Dept Med, Stockholm, Sweden

[17] Karolinska Univ Hosp Solna, Rheumatol Unit, Dept Med, Karolinska Inst, Stockholm, Sweden

[18] Osped Casa Sollievo Sofferenza, Ist Ricovero & Cura Carattere Sci, San Giovanni Rotondo, Italy

[19] Univ Montreal, Ctr Hosp Univ, Montreal, PQ, Canada

[20] Hop St Justine, Dept Gastroenterol, Montreal, PQ H3T 1C5, Canada

[21] Leiden Univ, Dept Gastroenterol & Hepatol, Med Ctr, Leiden, Netherlands

[22] Radboud Univ Nijmegen, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands

[23] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[24] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands

[25] Yale Univ, NIDDK, New Haven, CT USA

[26] Yale Univ, Dept Med, Sect Digest Dis, New Haven, CT 06520 USA

[27] Univ Toronto, Mt Sinai Hosp, Ctr Inflammatory Bowel Dis, Toronto, ON M5G 1X5, Canada

[28] Yale Univ, Dept Genet, New Haven, CT USA

[29] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[30] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[31] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[32] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA

[33] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA

[34] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[35] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[36] Univ Washington, Dept Gen Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[37] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

[38] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden

[39] Singapore Gen Hosp, Lab Inflammat Biol, Singapore 0316, Singapore

[40] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA

[41] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 04期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

GENETIC-VARIANTS; CROHNS-DISEASE; RISK; CONTRIBUTE; IMMUNITY;

D O I：

10.1038/ng.549

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan(1), comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

引用

页码：332 / U88

页数：8

共 27 条

[1]

A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population [J].

Asano, Kouichi ;

Matsushita, Tomonaga ;

Umeno, Junji ;

Hosono, Naoya ;

Takahashi, Atsushi ;

Kawaguchi, Takahisa ;

Matsumoto, Takayuki ;

Matsui, Toshiyuki ;

Kakuta, Yoichi ;

Kinouchi, Yoshitaka ;

Shimosegawa, Tooru ;

Hosokawa, Masayo ;

Arimura, Yoshiaki ;

Shinomura, Yasuhisa ;

Kiyohara, Yutaka ;

Tsunoda, Tatsuhiko ;

Kamatani, Naoyuki ;

Iida, Mitsuo ;

Nakamura, Yusuke ;

Kubo, Michiaki .

NATURE GENETICS, 2009, 41 (12) :1325-U92

[2]

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[3]

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region [J].

Barrett, Jeffrey C. ;

Lee, James C. ;

Lees, Charles W. ;

Prescott, Natalie J. ;

Anderson, Carl A. ;

Phillips, Anne ;

Wesley, Emma ;

Parnell, Kirstie ;

Zhang, Hu ;

Drummond, Hazel ;

Nimmo, Elaine R. ;

Massey, Dunecan ;

Blaszczyk, Kasia ;

Elliott, Timothy ;

Cotterill, Lynn ;

Dallal, Helen ;

Lobo, Alan J. ;

Mowat, Craig ;

Sanderson, Jeremy D. ;

Jewell, Derek P. ;

Newman, William G. ;

Edwards, Cathryn ;

Ahmad, Tariq ;

Mansfield, John C. ;

Satsangi, Jack ;

Parkes, Miles ;

Mathew, Christopher G. ;

Donnelly, Peter ;

Peltonen, Leena ;

Blackwell, Jenefer M. ;

Bramon, Elvira ;

Brown, Matthew A. ;

Casas, Juan P. ;

Corvin, Aiden ;

Craddock, Nicholas ;

Deloukas, Panos ;

Duncanson, Audrey ;

Jankowski, Janusz ;

Markus, Hugh S. ;

McCarthy, Mark I. ;

Palmer, Colin N. A. ;

Plomin, Robert ;

Rautanen, Anna ;

Sawcer, Stephen J. ;

Samani, Nilesh ;

Trembath, Richard C. ;

Viswanathan, Ananth C. ;

Wood, Nicholas ;

Spencer, Chris C. A. ;

Bellenguez, Celine .

NATURE GENETICS, 2009, 41 (12) :1330-U99

[4]

Phospholipase A2 structure/function, mechanism, and signaling [J].

Burke, John E. ;

Dennis, Edward A. .

JOURNAL OF LIPID RESEARCH, 2009, 50 :S237-S242

[5]

Practical aspects of imputation-driven meta-analysis of genome-wide association studies [J].

de Bakker, Paul I. W. ;

Ferreira, Manuel A. R. ;

Jia, Xiaoming ;

Neale, Benjamin M. ;

Raychaudhuri, Soumya ;

Voight, Benjamin F. .

HUMAN MOLECULAR GENETICS, 2008, 17 :R122-R128

[6]

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease [J].

Fisher, Sheila A. ;

Tremelling, Mark ;

Anderson, Carl A. ;

Gwilliam, Rhian ;

Bumpstead, Suzannah ;

Prescott, Natalie J. ;

Nimmo, Elaine R. ;

Massey, Dunecan ;

Berzuini, Carlo ;

Johnson, Christopher ;

Barrett, Jeffrey C. ;

Cummings, Fraser R. ;

Drummond, Hazel ;

Lees, Charlie W. ;

Onnie, Clive M. ;

Hanson, Catherine E. ;

Blaszczyk, Katarzyna ;

Inouye, Mike ;

Ewels, Philip ;

Ravindrarajah, Radhi ;

Keniry, Andrew ;

Hunt, Sarah ;

Carter, Martyn ;

Watkins, Nick ;

Ouwehand, Willem ;

Lewis, Cathryn M. ;

Cardon, Lon ;

Lobo, Alan ;

Forbes, Alastair ;

Sanderson, Jeremy ;

Jewell, Derek P. ;

Mansfield, John C. ;

Deloukas, Panos ;

Mathew, Christopher G. ;

Parkes, Miles ;

Satsangi, Jack .

NATURE GENETICS, 2008, 40 (06) :710-712

[7]

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility [J].

Franke, Andre ;

Balschun, Tobias ;

Karlsen, Tom H. ;

Sventoraityte, Jurgita ;

Nikolaus, Susanna ;

Mayr, Gabriele ;

Domingues, Francisco S. ;

Albrecht, Mario ;

Nothnagel, Michael ;

Ellinghaus, David ;

Sina, Christian ;

Onnie, Clive M. ;

Weersma, Rinse K. ;

Stokkers, Pieter C. F. ;

Wijmenga, Cisca ;

Gazouli, Maria ;

Strachan, David ;

McArdle, Wendy L. ;

Vermeire, Severine ;

Rutgeerts, Paul ;

Rosenstiel, Philip ;

Krawczak, Michael ;

Vatn, Morten H. ;

Mathew, Christopher G. ;

Schreiber, Stefan .

NATURE GENETICS, 2008, 40 (11) :1319-1323

[8]

Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis [J].

Franke, Andre ;

Balschun, Tobias ;

Karlsen, Tom H. ;

Hedderich, Juergen ;

May, Sandra ;

Lu, Tim ;

Schuldt, Doerthe ;

Nikolaus, Susanna ;

Rosenstiel, Philip ;

Krawczak, Michael ;

Schreiber, Stefan .

NATURE GENETICS, 2008, 40 (06) :713-715

[9]

Systematic Association Mapping Identifies NELL1 as a Novel IBD Disease Gene [J].

Franke, Andre ;

Hampe, Jochen ;

Rosenstiel, Philip ;

Becker, Christian ;

Wagner, Florian ;

Haesler, Robert ;

Little, Randall D. ;

Huse, Klaus ;

Ruether, Andreas ;

Balschun, Tobias ;

Wittig, Michael ;

ElSharawy, Abdou ;

Mayr, Gabriele ;

Albrecht, Mario ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fournier, Helene ;

Keith, Tim ;

Radelof, Uwe ;

Platzer, Matthias ;

Mathew, Christopher G. ;

Stoll, Monika ;

Krawczak, Michael ;

Nuernberg, Peter ;

Schreiber, Stefan .

PLOS ONE, 2007, 2 (08)

[10]

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis [J].

Goyette, P. ;

Lefebvre, C. ;

Ng, A. ;

Brant, S. R. ;

Cho, J. H. ;

Duerr, R. H. ;

Silverberg, M. S. ;

Taylor, K. D. ;

Latiano, A. ;

Aumais, G. ;

Deslandres, C. ;

Jobin, G. ;

Annese, V. ;

Daly, M. J. ;

Xavier, R. J. ;

Rioux, J. D. .

MUCOSAL IMMUNOLOGY, 2008, 1 (02) :131-138

← 1 2 3 →