Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

被引：3530

作者：

Jostins, Luke ^{[2
]}

Ripke, Stephan ^{[3
,4
]}

Weersma, Rinse K. ^{[5
]}

Duerr, Richard H. ^{[7
,8
]}

McGovern, Dermot P. ^{[9
,10
,11
]}

Hui, Ken Y. ^{[1
]}

Lee, James C. ^{[12
]}

Schumm, L. Philip ^{[13
]}

Sharma, Yashoda ^{[14
]}

Anderson, Carl A. ^{[2
]}

Essers, Jonah ^{[15
]}

Mitrovic, Mitja ^{[6
,16
]}

Ning, Kaida ^{[14
]}

Cleynen, Isabelle ^{[17
]}

Theatre, Emilie ^{[18
,19
,20
]}

Spain, Sarah L. ^{[21
]}

Raychaudhuri, Soumya ^{[22
,23
,24
]}

Goyette, Philippe ^{[25
,26
]}

Wei, Zhi ^{[27
]}

Abraham, Clara ^{[14
]}

Achkar, Jean-Paul ^{[28
,29
]}

Ahmad, Tariq ^{[30
]}

Amininejad, Leila ^{[31
]}

Ananthakrishnan, Ashwin N. ^{[32
]}

Andersen, Vibeke ^{[33
]}

Andrews, Jane M. ^{[34
,35
]}

Baidoo, Leonard ^{[7
]}

Balschun, Tobias ^{[36
]}

Bampton, Peter A. ^{[37
,38
]}

Bitton, Alain ^{[39
]}

Boucher, Gabrielle ^{[25
,26
]}

Brand, Stephan ^{[40
]}

Buening, Carsten ^{[41
]}

Cohain, Ariella ^{[42
]}

Cichon, Sven ^{[43
]}

D'Amato, Mauro ^{[44
]}

De Jong, Dirk ^{[5
]}

Devaney, Kathy L. ^{[32
]}

Dubinsky, Marla ^{[45
]}

Edwards, Cathryn ^{[46
]}

Ellinghaus, David ^{[36
]}

Ferguson, Lynnette R. ^{[47
]}

Franchimont, Denis ^{[31
]}

Fransen, Karin ^{[7
,48
]}

Gearry, Richard ^{[49
,50
]}

Georges, Michel ^{[18
,19
]}

Gieger, Christian ^{[51
]}

Glas, Juergen ^{[39
]}

Haritunians, Talin ^{[11
]}

Hart, Ailsa ^{[52
]}

机构：

[1] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA

[2] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England

[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Univ Groningen, Dept Gastroenterol & Hepatol, NL-9700 RB Groningen, Netherlands

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[7] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15261 USA

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

[9] F Widjaja Fdn Inflammatory Bowel, Los Angeles, CA 90048 USA

[10] Immunobiol Res Inst, Los Angeles, CA 90048 USA

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

[12] Univ Cambridge, Addenbrookes Hosp, Inflammatory Bowel Dis Res Grp, Cambridge CB2 0QQ, England

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

[14] Yale Univ, Sch Med, Dept Internal Med, Sect Digest Dis, New Haven, CT 06520 USA

[15] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[16] Univ Maribor, Fac Med, Ctr Human Mol Genet & Pharmacogen, SLO-2000 Maribor, Slovenia

[17] Katholieke Univ Leuven, Gastroenterol Sect, Dept Clin & Expt Med, B-3000 Louvain, Belgium

[18] Univ Liege, Grp Interdisciplinaire Genoprote Appl GIGA R, Unit Anim Genom, B-4000 Liege, Belgium

[19] Univ Liege, Fac Vet Med, B-4000 Liege, Belgium

[20] Univ Liege, Ctr Hosp Univ, Div Gastroenterol, B-4000 Liege, Belgium

[21] Kings Coll London, Dept Med & Mol Genet, Div Genet & Mol Med, Sch Med,Guys Hosp, London SE1 9RT, England

[22] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[23] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[24] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[25] Univ Montreal, Montreal, PQ H1T 1C8, Canada

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

[27] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA

[28] Cleveland Clin, Dept Gastroenterol & Hepatol, Inst Digest Dis, Cleveland, OH 44195 USA

[29] Cleveland Clin, Lerner Res Inst, Dept Pathobiol, Cleveland, OH 44195 USA

[30] Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England

[31] Free Univ Brussels, Erasmus Hosp, Dept Gastroenterol, B-1070 Brussels, Belgium

[32] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA 02114 USA

[33] Viborg Reg Hosp, Dept Med, DK-8800 Viborg, Denmark

[34] Royal Adelaide Hosp, Dept Gastroenterol & Hepatol, Inflammatory Bowel Dis Serv, Adelaide, SA 5000, Australia

[35] Univ Adelaide, Sch Med, Adelaide, SA 5000, Australia

[36] Univ Kiel, Inst Clin Chem, D-24105 Kiel, Germany

[37] Flinders Med Ctr, Dept Gastroenterol & Hepatol, Adelaide, SA 5000, Australia

[38] Flinders Univ S Australia, Sch Med, Adelaide, SA 5000, Australia

[39] McGill Univ, Ctr Hlth, Div Gastroenterol, Royal Victoria Hosp, Montreal, PQ H3A 1A1, Canada

[40] Univ Munich, Univ Hosp Munich Grosshadern, Dept Med 2, D-80336 Munich, Germany

[41] Univ Med Berlin, Charite, Dept Gastroenterol, D-10117 Berlin, Germany

[42] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA

[43] Univ Hosp Bonn, Life & Brain Ctr, Dept Genom, D-53012 Bonn, Germany

[44] Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden

[45] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA

[46] Torbay Hosp, Dept Gastroenterol, Torquay TQ2 7AA, Devon, England

[47] Univ Auckland, Fac Med & Hlth Sci, Sch Med Sci, Auckland 1142, New Zealand

[48] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen T, Netherlands

[49] Univ Otago, Dept Med, Christchurch 8140, New Zealand

[50] Christchurch Hosp, Dept Gastroenterol, Christchurch 8011, New Zealand

来源：

NATURE | 2012年 / 491卷 / 7422期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

HYPER-IGE SYNDROME; RISK LOCI; SUSCEPTIBILITY; EXPRESSION; METAANALYSIS; TUBERCULOSIS; MUTATIONS; NETWORK; NUMBER;

D O I：

10.1038/nature11582

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

引用

页码：119 / 124

页数：6

共 30 条

[1] Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 [J].

Anderson, Carl A. ;

Boucher, Gabrielle ;

Lees, Charlie W. ;

Franke, Andre ;

D'Amato, Mauro ;

Taylor, Kent D. ;

Lee, James C. ;

Goyette, Philippe ;

Imielinski, Marcin ;

Latiano, Anna ;

Lagace, Caroline ;

Scott, Regan ;

Amininejad, Leila ;

Bumpstead, Suzannah ;

Baidoo, Leonard ;

Baldassano, Robert N. ;

Barclay, Murray ;

Bayless, Theodore M. ;

Brand, Stephan ;

Buening, Carsten ;

Colombel, Jean-Frederic ;

Denson, Lee A. ;

De Vos, Martine ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Ellinghaus, David ;

Fehrmann, Rudolf S. N. ;

Floyd, James A. B. ;

Florin, Timothy ;

Franchimont, Denis ;

Franke, Lude ;

Georges, Michel ;

Glas, Juergen ;

Glazer, Nicole L. ;

Guthery, Stephen L. ;

Haritunians, Talin ;

Hayward, Nicholas K. ;

Hugot, Jean-Pierre ;

Jobin, Gilles ;

Laukens, Debby ;

Lawrance, Ian ;

Lemann, Marc ;

Levine, Arie ;

Libioulle, Cecile ;

Louis, Edouard ;

McGovern, Dermot P. ;

Milla, Monica ;

Montgomery, Grant W. ;

Morley, Katherine I. ;

Mowat, Craig .

NATURE GENETICS, 2011, 43 (03) :246-U94

[2] Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes [J].

Bhattacharjee, Ashish ;

Pal, Srabani ;

Feldman, Gerald M. ;

Cathcart, Martha K. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (42) :36709-36723

[3] Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases [J].

Bustamante, Jacinta ;

Picard, Capucine ;

Boisson-Dupuis, Stephanie ;

Abel, Laurent ;

Casanova, Jean-Laurent .

YEAR IN HUMAN AND MEDICAL GENETICS: INBORN ERRORS OF IMMUNITY II, 2011, 1246 :92-101

[4] Variations in DNA elucidate molecular networks that cause disease [J].

Chen, Yanqing ;

Zhu, Jun ;

Lum, Pek Yee ;

Yang, Xia ;

Pinto, Shirly ;

MacNeil, Douglas J. ;

Zhang, Chunsheng ;

Lamb, John ;

Edwards, Stephen ;

Sieberts, Solveig K. ;

Leonardson, Amy ;

Castellini, Lawrence W. ;

Wang, Susanna ;

Champy, Marie-France ;

Zhang, Bin ;

Emilsson, Valur ;

Doss, Sudheer ;

Ghazalpour, Anatole ;

Horvath, Steve ;

Drake, Thomas A. ;

Lusis, Aldons J. ;

Schadt, Eric E. .

NATURE, 2008, 452 (7186) :429-435

[5] Genomics and the Multifactorial Nature of Human Autoimmune Disease [J].

Cho, Judy H. ;

Gregersen, Peter K. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 365 (17) :1612-1623

[6] Promise and pitfalls of the Immunochip [J].

Cortes, Adrian ;

Brown, Matthew A. .

ARTHRITIS RESEARCH & THERAPY, 2011, 13 (01)

[7] Genetics of gene expression and its effect on disease [J].

Emilsson, Valur ;

Thorleifsson, Gudmar ;

Zhang, Bin ;

Leonardson, Amy S. ;

Zink, Florian ;

Zhu, Jun ;

Carlson, Sonia ;

Helgason, Agnar ;

Walters, G. Bragi ;

Gunnarsdottir, Steinunn ;

Mouy, Magali ;

Steinthorsdottir, Valgerdur ;

Eiriksdottir, Gudrun H. ;

Bjornsdottir, Gyda ;

Reynisdottir, Inga ;

Gudbjartsson, Daniel ;

Helgadottir, Anna ;

Jonasdottir, Aslaug ;

Jonasdottir, Adalbjorg ;

Styrkarsdottir, Unnur ;

Gretarsdottir, Solveig ;

Magnusson, Kristinn P. ;

Stefansson, Hreinn ;

Fossdal, Ragnheidur ;

Kristjansson, Kristleifur ;

Gislason, Hjortur G. ;

Stefansson, Tryggvi ;

Leifsson, Bjorn G. ;

Thorsteinsdottir, Unnur ;

Lamb, John R. ;

Gulcher, Jeffrey R. ;

Reitman, Marc L. ;

Kong, Augustine ;

Schadt, Eric E. ;

Stefansson, Kari .

NATURE, 2008, 452 (7186) :423-U2

[8] 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

[9] Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci [J].

Franke, Andre ;

McGovern, Dermot P. B. ;

Barrett, Jeffrey C. ;

Wang, Kai ;

Radford-Smith, Graham L. ;

Ahmad, Tariq ;

Lees, Charlie W. ;

Balschun, Tobias ;

Lee, James ;

Roberts, Rebecca ;

Anderson, Carl A. ;

Bis, Joshua C. ;

Bumpstead, Suzanne ;

Ellinghaus, David ;

Festen, Eleonora M. ;

Georges, Michel ;

Green, Todd ;

Haritunians, Talin ;

Jostins, Luke ;

Latiano, Anna ;

Mathew, Christopher G. ;

Montgomery, Grant W. ;

Prescott, Natalie J. ;

Raychaudhuri, Soumya ;

Rotter, Jerome I. ;

Schumm, Philip ;

Sharma, Yashoda ;

Simms, Lisa A. ;

Taylor, Kent D. ;

Whiteman, David ;

Wijmenga, Cisca ;

Baldassano, Robert N. ;

Barclay, Murray ;

Bayless, Theodore M. ;

Brand, Stephan ;

Buening, Carsten ;

Cohen, Albert ;

Colombel, Jean-Frederick ;

Cottone, Mario ;

Stronati, Laura ;

Denson, Ted ;

De Vos, Martine ;

D'Inca, Renata ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Florin, Tim ;

Franchimont, Denis ;

Gearry, Richard ;

Glas, Juergen ;

Van Gossum, Andre .

NATURE GENETICS, 2010, 42 (12) :1118-+

[10] Infant colitis-it's in the genes [J].

Glocker, Erik-Oliver ;

Frede, Natalie ;

Perro, Mario ;

Sebire, Neil ;

Elawad, Mamoun ;

Shah, Neil ;

Grimbacher, Bodo .

LANCET, 2010, 376 (9748) :1272-1272

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