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

被引：414

作者：

Barrett, Jeffrey C. ^{[1
]}

Lee, James C. ^{[2
]}

Lees, Charles W. ^{[3
]}

Prescott, Natalie J. ^{[4
]}

Anderson, Carl A. ^{[1
,5
]}

Phillips, Anne ^{[3
]}

Wesley, Emma ^{[6
]}

Parnell, Kirstie ^{[6
]}

Zhang, Hu ^{[2
]}

Drummond, Hazel ^{[3
]}

Nimmo, Elaine R. ^{[3
]}

Massey, Dunecan ^{[2
]}

Blaszczyk, Kasia ^{[4
]}

Elliott, Timothy ^{[7
]}

Cotterill, Lynn ^{[8
,9
]}

Dallal, Helen ^{[10
]}

Lobo, Alan J. ^{[11
]}

Mowat, Craig

Sanderson, Jeremy D. ^{[7
]}

Jewell, Derek P. ^{[12
]}

Newman, William G. ^{[9
]}

Edwards, Cathryn ^{[13
]}

Ahmad, Tariq ^{[6
]}

Mansfield, John C. ^{[14
]}

Satsangi, Jack ^{[3
]}

Parkes, Miles ^{[2
]}

Mathew, Christopher G. ^{[4
]}

Donnelly, Peter ^{[5
,15
]}

Peltonen, Leena ^{[1
]}

Blackwell, Jenefer M. ^{[16
]}

Bramon, Elvira ^{[17
,18
]}

Brown, Matthew A. ^{[19
]}

Casas, Juan P. ^{[20
]}

Corvin, Aiden ^{[21
]}

Craddock, Nicholas ^{[22
]}

Deloukas, Panos ^{[1
]}

Duncanson, Audrey ^{[23
]}

Jankowski, Janusz ^{[24
]}

Markus, Hugh S. ^{[25
]}

McCarthy, Mark I. ^{[26
]}

Palmer, Colin N. A. ^{[27
]}

Plomin, Robert ^{[28
]}

Rautanen, Anna ^{[5
]}

Sawcer, Stephen J. ^{[29
]}

Samani, Nilesh ^{[30
]}

Trembath, Richard C. ^{[4
]}

Viswanathan, Ananth C. ^{[31
,32
]}

Wood, Nicholas ^{[33
]}

Spencer, Chris C. A. ^{[5
]}

Bellenguez, Celine ^{[5
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge, England

[2] Addenbrookes Hosp, Gastroenterol Res Unit, Cambridge, England

[3] Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Gastrointestinal Unit, Edinburgh, Midlothian, Scotland

[4] Kings Coll London, Guys Hosp, Sch Med, Dept Med & Mol Genet, London WC2R 2LS, England

[5] Wellcome Trust Ctr Human Genet, Oxford, England

[6] Peninsula Coll Med & Dent, Exeter, Devon, England

[7] St Thomas Hosp, Dept Gastroenterol, Guys & St Thomas NHS Fdn Trust, London, England

[8] Univ Manchester, Dept Med Genet, MAHSC, Manchester, Lancs, England

[9] Cent Manchester NHS Fdn Trust, NIHR Biomed Res Ctr, Manchester, Lancs, England

[10] S Tees Hosp NHS Trust, James Cook Univ Hosp, Dept Gastroenterol, Middlesbrough, Cleveland, England

[11] Univ Sheffield, Royal Hallamshire Hosp, Sch Med, Div Mol & Genet Med, Sheffield S10 2JF, S Yorkshire, England

[12] Radcliffe Infirm, Gastroenterol Unit, Gibson Labs, Oxford OX2 6HE, England

[13] Torbay Hosp, Endoscopy Reg Training Unit, Torquay, England

[14] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[15] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[16] Addenbrookes Hosp, Cambridge Inst Med Res, Genet & Infect Lab, Cambridge, England

[17] Kings Coll London, Inst Psychiat, Biomed Res Ctr Mental Hlth, Div Psychol Med & Psychiat, London WC2R 2LS, England

[18] S London & Maudsley NHS Fdn Trust, London, England

[19] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst Canc Immunol & Metab Med, Brisbane, Qld, Australia

[20] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England

[21] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland

[22] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales

[23] Wellcome Trust Res Labs, Mol & Physiol Sci, London, England

[24] Barts & London Queen Marys Sch Med & Dent, Ctr Gastroenterol, London, England

[25] St Georges Univ London, London, England

[26] Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab ICDEM, Oxford OX3 7LJ, England

[27] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland

[28] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England

[29] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[30] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

[31] Moorfields Eye Hosp, NHS Fdn Trust, Glaucoma Res Unit, London, England

[32] UCL, Dept Genet, Inst Ophthalmol, London, England

[33] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[34] Univ Cambridge, Dept Haematol, Cambridge, England

[35] NHS Blood & Transplant, Cambridge, England

[36] Univ Bristol, Dept Social Med, Avon Longitudinal Study Parents & Children DNA Ba, Bristol, Avon, England

[37] Dept Social Med, ALSPAC Lab, Cambridge, England

[38] St George Hosp, Div Community Hlth Sci, London, England

来源：

NATURE GENETICS | 2009年 / 41卷 / 12期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

INFLAMMATORY-BOWEL-DISEASE; INTESTINAL EPITHELIAL-CELLS; CROHNS-DISEASE; E-CADHERIN; COLORECTAL-CANCER; SEQUENCE VARIANTS; NUCLEAR FACTOR-4; RISK LOCI; GENE; EXPRESSION;

D O I：

10.1038/ng.483

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

引用

页码：1330 / U99

页数：7

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