Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

A. Franke; D. P. B.  McGovern; J. C.  Barrett; K. Wang; G. L.  Radford-Smith; T.  Ahmad; C. W.  Lees; T. Balschun; J. Lee; R. Roberts; C. A. Anderson; J. C.  Bis; S.  Bumpstead; D.  Ellinghaus; E. M. Festen; M.  Georges; T.  Green; T. Haritunians; L. Jostins; A. Latiano; C. G.  Mathew; G. W.  Montgomery; N. J.  Prescott; S.  Raychaudhuri; J. I.  Rotter; P.  Schumm; Y. Sharma; L. A.  Simms; K. D.  Taylor; D.  Whiteman; C. Wijmenga; R. N.  Baldassano; M. Barclay; T. M.  Bayless; S.  Brand; C.  Buning; A. Cohen; J-F. Colombel; M. Cottone; L. Stronati; T. Denson; M. De Vos; R. D'Inca; M. Dubinsky; C. Edwards; T. Florin; D. Franchimont; R. Gearry; J. Glas; A. Van Gossum; S. L. Guthery; J.  Halfvarson; H. W.  Verspaget; J-P.  Hugot; A. Karban; D. Laukens; I. Lawrance; M. Lemann; A. Levine; C. Libioulle; E. Louis; C. Mowat; W. Newman; J. Panes; A. Phillips; D. D.  Proctor; M. Regueiro; R. Russell; P. Rutgeerts; J. Sanderson; M. Sans; F. Seibold; A. H.  Steinhart; P. C. F.  Stokkers; L.  Torkvist; G. Kullak-Ublick; D. Wilson; T.  Walters; S. R.  Targan; S. R.  Brant; J. D.  Rioux; M.  D'Amato; R.  Weersma; Subramaniam Kugathasan; A. M.  Griffiths; J. C.  Mansfield; S. Vermeire; R. H.  Duerr; M. S.  Silverberg; J.  Satsangi; S. Schreiber; J. H.  Cho; V.  Annese; H.  Hakonarson; M. J.  Daly; M.  Parkes

About this item:

102 Views | 51 Downloads

Author Notes:

Correspondence: Miles Parkes, Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom, miles.parkes@addenbrooks.nhs.uk, Tel.: +44 (0) 1223-216389, Fax: +44 (0) 1223 596213

AF, DPBM, GRS, TA, JL, RR, JB, TH, AL, CGM, NP, JIR, PS, YS, LS, KDT, DW, CW, GKU, JDR, MD’A, RW, SV, RHD, JS, SS, VA, HH were involved in establishing DNA collections, and/or assembling phenotypic data.

AF, DE, JCB, KW, TG, SR, CAA, LJ, MJD performed statistical analyses.

DPBM, GRS, CWL, EMF, RNB, MB, TMB, SB, CB, AC, J-FC, MC, SC, TD, MdV, RD’I, MD, CE, TF, DF, RG, JG, AVG, SLG, JH, DH, J-PH, DL, IL, ML, AL, CL, EL, CM, WN, JP, AP, DDP, MR, PR, JS, MS, FS, AHS, PCFS, SRT, LT, TW, SRB, RW, SK, AMG, JCM, SV, RHD, MSS, JS, SS, JHC, VA recruited patients.

AF, DPBM, TB, SB, KT, MG, GM supervised laboratory work.

AF, DPBM, JCB, KW, SB, RHD, JS, SS, JHC, MJD, MP contributed to writing the manuscript. All authors read and approved the final manuscript before submission.

We thank all subjects who contributed samples, and physicians and nursing staff who helped with recruitment globally.

We acknowledge the Wellcome Trust Case Control Consortium. We thank the 1958 British Birth Cohort and Banco Nacional de ADN, Salamanca, Spain who supplied control DNA samples.

Other significant contributors: K. Hanigan, Z.-Z. Zhao, N. Huang, P. Webb, N. Hayward, A. Rutherford, R. Gwilliam, J. Ghori, D Strachan, W. McCardle, W. Ouwehand, M. Newsky, S. Ehlers, I. Pauselius, K. Holm, C. Sina, L. Baidoo, A. Andriulli and M.C. Renda

All authors declare no financial interest.

Subjects:

Research Funding:

his study was supported by the German Ministry of Education and Research through the National Genome Research Network and infrastructure support through the DFG cluster of excellence “Inflammation at Interfaces”.

Also the Italian Ministry for Health GR-2008-1144485, with case collections supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition.

We acknowledge funding provided by Royal Brisbane and Women’s Hospital Foundation; University of Queensland (Ferguson Fellowship); National Health and Medical Research Council, Australia and by the European Community (5th PCRDT) and by the European Crohn’s and Colitis Organization.

UK case collections were supported by the National Association for Colitis and Crohn’s disease, Wellcome Trust, Medical Research Council UK and Peninsular College of Medicine and Dentistry, Exeter.

We also acknowledge the NIHR Biomedical Research Centre awards to Guy’s & St Thomas’ NHS Trust / King’s College London and to Addenbrooke’s Hospital / University of Cambridge School of Clinical Medicine.

The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 & DK064869 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.B.M.), DK76984 (MD), and DK084554 (MD and DPBM), and DK062429 (J.H.C.).

J.H.C. is also funded by the Crohn’s and Colitis Foundation of America; and SLG by DK069513 and Primary Children’s Medical Center Foundation.

edars Sinai supported by NCRR grant M01-RR00425; NIH/NIDDK grant P01-DK046763; DK 063491; and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds.

RW is supported by a clinical fellow grant (90700281) from the Netherlands Organization for Scientific Research; EL, DF and SV are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium.

SB was supported by the “Deutsche Forschungsgemeinschaft” (DFG; BR 1912/5-1).

JCB is supported by Wellcome Trust grant WT089120/Z/09/Z. Replication genotyping was supported by unrestricted grants from Abbott Laboratories Ltd and Giuliani SpA.

he CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke.

Keywords:

Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Inflammatory bowel disease
Sequence variants
Common variants
NEDD4 family
Association
Gene
Identification
Activation
Contribute
Autophagy

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

A. Franke, University of Kiel

D. P. B. McGovern, Cedars Sinai Medical Center

J. C. Barrett, Wellcome Trust Sanger Institute

K. Wang, Childrens Hospital of Philadelphia

G. L. Radford-Smith, Queensland Institute of Medical Research

T. Ahmad, Peninsula College

C. W. Lees, University of Edinburgh

T. Balschun, University of Kiel

J. Lee, University of Cambridge

R. Roberts, University of Otago

C. A. Anderson, Wellcome Trust Sanger Institute

J. C. Bis, University of Washington

S. Bumpstead, Wellcome Trust Sanger Institute

D. Ellinghaus, University of Kiel

E. M. Festen, University of Groningen

M. Georges, University of Liege

T. Green, Harvard University

T. Haritunians, Cedars Sinai Medical Center

L. Jostins, Wellcome Trust Sanger Institute

A. Latiano, IRCCS CSS Hospital

C. G. Mathew, King's College London

G. W. Montgomery, Queensland Institute of Medical Research

N. J. Prescott, King's College London

S. Raychaudhuri, Harvard University

J. I. Rotter, Cedars Sinai Medical Center

P. Schumm, University of Chicago

Y. Sharma, Yale University

L. A. Simms, Queensland Institute of Medical Research

K. D. Taylor, Cedars Sinai Medical Center

D. Whiteman, Queensland Institute of Medical Research

C. Wijmenga, University of Groningen

R. N. Baldassano, Childrens Hospital of Philadelphia

M. Barclay, University of Otago

T. M. Bayless, Johns Hopkins University

S. Brand, University of Munich

C. Buning, Universitätsmedizin Berlin

A. Cohen, Montreal Jewish General Hospital

J-F. Colombel, Université de Lille

M. Cottone, Cervello Hospital, Italy

L. Stronati, ENEA, Department of Biology of Radiations and Human Health, Rome, Italy

T. Denson, Cincinnati Childrens Hospital Medical Center

M. De Vos, Ghent University

R. D'Inca, University Hospital Padua, Italy

M. Dubinsky, Cedars Sinai Medical Center

C. Edwards, Torbay Hospital, UK

T. Florin, Mater Health Services, Australia

D. Franchimont, Free University of Brussels

R. Gearry, University of Otago

J. Glas, University of Munich

A. Van Gossum, Free University of Brussels

S. L. Guthery, University of Utah

J. Halfvarson, Orebro University Hospital

H. W. Verspaget, Leiden University

J-P. Hugot, Université Paris Diderot

A. Karban, Technion Israel Institute of Technology

D. Laukens, Ghent University

I. Lawrance, University of Western Australia

M. Lemann, Université Paris Diderot

A. Levine, Tel Aviv University

C. Libioulle, University of Liege

E. Louis, University of Liege

C. Mowat, University of Dundee

W. Newman, University of Manchester

J. Panes, Hospital Clinic Barcelona

A. Phillips, University of Dundee

D. D. Proctor, Yale University

M. Regueiro, University of Pittsburgh

R. Russell, Yorkhill Hosp

P. Rutgeerts, Univ Hosp Gasthuisberg

J. Sanderson, St Thomas Hosp

M. Sans, Hospital Clinic Barcelona

F. Seibold, University of Bern

A. H. Steinhart, University of Toronto

P. C. F. Stokkers, University of Amsterdam

L. Torkvist, Karolinska Institutet

G. Kullak-Ublick, University of Zurich

D. Wilson, University of Edinburgh

T. Walters, University of Toronto

S. R. Targan, Cedars Sinai Medical Center

S. R. Brant, Johns Hopkins University

J. D. Rioux, University of Montreal

M. D'Amato, Karolinska Institutet

R. Weersma, University of Groningen

Subramaniam Kugathasan, Emory University

A. M. Griffiths, University of Toronto

J. C. Mansfield, University of Newcastle

S. Vermeire, University of Leuven

R. H. Duerr, University of Pittsburgh

M. S. Silverberg, University of Toronto

J. Satsangi, University of Edinburgh

S. Schreiber, University of Kiel

J. H. Cho, Yale University

V. Annese, IRCCS CSS Hospital

H. Hakonarson, Childrens Hospital of Philadelphia

M. J. Daly, Harvard University

M. Parkes, University of Cambridge

Show all authors Show less authors

Tools:

Journal Title:

Nature Genetics

Volume:

Volume 42, Number 12

Publisher:

Nature Publishing Group | 2010-12-01, Pages 1118-1126

Type of Work:

Article | Post-print: After Peer Review

Permanent URL:

https://pid.emory.edu/ark:/25593/vm78x

Publisher DOI:

http://doi.org/10.1038/ng.717

Abstract:

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10 -8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

Copyright information:

Export to EndNote

Undergraduate

Community

Graduate

Libraries

Library Tools

Resources

Resources

About this item:

Author Notes:

Subjects:

Research Funding:

Keywords:

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

Tools:

Abstract:

Copyright information: