Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis (original) (raw)

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Acknowledgements

We thank the patients and their families for participating in these studies. We are grateful to all of the clinicians, research nurses and study coordinators for their contributions to the work. We thank D. Caplan, G. Charron, C. Labbé, C. Lefebvre and D. Miclaus for their help in the preparation of the manuscript; J. Adams for help with immunohistochemistry; A. Landry for expression studies and D. Altshuler for his critical reading of the manuscript. The NIDDK IBDGC is funded by the following grants: DK62431 (S.R.B.), DK62420 (R.H.D.), DK62432 (J.D.R.), DK62423 (M.S.S.), DK62413 (K.D.T.) and DK62422 and DK62429 (J.H.C.). The work on the Cedars-Sinai cohort was supported by project 1 of DK 46763 (J.I.R.). R.J.X. is supported by the following grants: AI062773 and DK43351.

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Author notes

1. Judy H Cho, Mark J Daly and Steven R Brant: These authors contributed equally to this work.

Authors and Affiliations

1. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, H1T 1C8, Quebec, Canada
   John D Rioux & Philippe Goyette
2. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA
   John D Rioux, Todd Green & Mark J Daly
3. Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA
   Ramnik J Xavier, Alan Huett & Petric Kuballa
4. Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, 8700 W. Beverly Blvd., Los Angeles, 90048, California, USA
   Kent D Taylor, Stephan R Targan, Andrew F Ippoliti, Ling Mei & Jerome I Rotter
5. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, M5G 1X5, Ontario, Canada
   Mark S Silverberg & A Hillary Steinhart
6. Department of Human Genetics, University of Pittsburgh, Graduate School of Public Health, 130 Desoto Street, Pittsburgh, 15261, Pennsylvania, USA
   M Michael Barmada & Richard H Duerr
7. Department of Medicine, Johns Hopkins University, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, 1503 East Jefferson Street, Baltimore, 21231, Maryland, USA
   Lisa Wu Datta & Steven R Brant
8. Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, 615 E. Wolfe Street, Baltimore, 21205, Maryland, USA
   Yin Yao Shugart & Steven R Brant
9. Department of Pediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada
   Anne M Griffiths
10. Université de Montréal and Centre Hospitalier Universitaire de l'Université de Montréal (CHUM), Hôtel-Dieu de Montréal, 3875 Saint Urbain Street, Montreal, H2W 1V1, Quebec, Canada
    Edmond-Jean Bernard
11. Department of Medicine, University of Chicago, 5801 South Ellis, Chicago, 60637, Illinois, USA
    Dan L Nicolae
12. Department of Medicine, Division of Gastroenterology, University of Pittsburgh, School of Medicine, Hepatology and Nutrition, University of Pittsburgh Medical Center (UPMC) Presbyterian, 200 Lothrop Street, Pittsburgh, 15213, Pennsylvania, USA
    Miguel Regueiro & Richard H Duerr
13. Department of Health Studies, University of Chicago, 5841 S. Maryland Avenue, Chicago, 60637, Illinois, USA
    L Philip Schumm
14. Department of Medicine, Division of Gastroenterology, Yale University, Inflammatory Bowel Disease (IBD) Center, 300 Cedar Street, New Haven, 06519, Connecticut, USA
    Judy H Cho
15. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA
    Mark J Daly

Authors

1. John D Rioux
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2. Ramnik J Xavier
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3. Kent D Taylor
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4. Mark S Silverberg
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5. Philippe Goyette
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6. Alan Huett
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7. Todd Green
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8. Petric Kuballa
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9. M Michael Barmada
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10. Lisa Wu Datta
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11. Yin Yao Shugart
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12. Anne M Griffiths
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13. Stephan R Targan
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14. Andrew F Ippoliti
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15. Edmond-Jean Bernard
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16. Ling Mei
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17. Dan L Nicolae
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18. Miguel Regueiro
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19. L Philip Schumm
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20. A Hillary Steinhart
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21. Jerome I Rotter
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22. Richard H Duerr
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23. Judy H Cho
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24. Mark J Daly
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25. Steven R Brant
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Contributions

S.R.B., J.H.C., R.H.D., E.-J. B., M.R., J.D.R., J.I.R., M.S., A.H.S., L.W.D, Y.Y.S. and K.D.T. collected patient samples and clinical information. S.R.B., J.H.C., M.J.D., R.H.D., J.D.R. and M.S. designed the genome-wide study. J.H.C., M.J.D., P.G., J.D.R., J.I.R., S.R.B. and K.D.T. designed the replication study. T.G. and P.G. analyzed the genome-wide and replication data, respectively, with contributions from M.M.B. and D.N., under the supervision of M.J.D. and J.D.R. L.M. analyzed the Cedars-Sinai ATG16L1 genetic data under the supervision of K.D.T. and J.I.R. P.K. and A.H. performed molecular and cellular biology experiments, under the supervision of R.J.X. The manuscript was written by M.J.D., J.D.R. and R.J.X., with contributions from S.R.B., J.H.C., R.H.D., M.S., A.H., P.G., A.H.S., Y.Y.S., D.L.N. and K.D.T. J.D.R. coordinated the analysis and manuscript writing efforts of this multicenter study.

Corresponding author

Correspondence toJohn D Rioux.

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Competing interests

A.H.S. is on the Scientific Advisory Boards of Shire Pharmaceuticals, Schering (Canada) and Procter & Gamble Pharmaceuticals.

R.H.D. has received honoraria for speaking in Illumina's educational seminar series about research projects that have used Illumina's products.

Supplementary information

Supplementary Fig. 1

Association and linkage disequilibrium patterns surrounding the ATG16L1, PHOX2B, 10q, NCF4 and FAM92B novel loci. (PDF 483 kb)

Supplementary Fig. 2

Conservation of the threonine allele at position 197 of the ATG16L1 gene. (PDF 18 kb)

Supplementary Fig. 3

PHOX2B expression is confined to a subset of gut cells in both mouse and human tissues. (PDF 2439 kb)

Supplementary Fig. 4

Expression pattern of NCF4 in primary immune cells. (PDF 10 kb)

Supplementary Fig. 5

Knockdown of ATG16L1 prevents induction of autophagy by classical stimuli. (PDF 347 kb)

Supplementary Fig. 6

Quality control assessment of the GWA data. (PDF 111 kb)

Supplementary Table 1

Phenotypic subgroup analysis of confirmed loci. (PDF 38 kb)

Supplementary Table 2

Primer sequences for real-time RT-PCR assays for RNA quantitation experiments. (PDF 14 kb)

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Rioux, J., Xavier, R., Taylor, K. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.Nat Genet 39, 596–604 (2007). https://doi.org/10.1038/ng2032

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• Received: 28 December 2006
• Accepted: 26 March 2007
• Published: 15 April 2007
• Issue Date: May 2007
• DOI: https://doi.org/10.1038/ng2032