Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2 (original) (raw)

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Acknowledgements

This work was supported in part by grants from the US National Heart, Lung and Blood Institute R01HL068927, R01HL068890, R01HL095396, the US National Institute of Diabetes and Digestive and Kidney Diseases R01DK066368, K23DK083551, P30DK027651, the US National Institute of Mental Health SOLAR-MH059490 and the US National Human Genome Research Institute HG-0004314; US Cystic Fibrosis Foundation grants CUTTIN00A0, CUTTIN06P0, COLLAC07A0, RDP-R025-CR07, KNOWLE00A0, RDP-R026-CR07, DRUMM0A00 and contract GENOMEQUEBEC07DDS0; Flight Attendant Medical Research Institute grant FAMRI2006; Lawson Wilkins Pediatric Endocrine Society grant LWPES Clinical Scholar Award; The Canadian Cystic Fibrosis Foundation; Genome Canada through the Ontario Genomics Institute as per research agreement 2004-OGI-3-05; Ontario Research Fund, Research Excellence Program; Lloyd Carr-Harris Foundation; and the Joint Fellowship of Canadian Institutes of Health Research and Ontario Women's Health Council. Funds for genome-wide genotyping were generously provided by the US Cystic Fibrosis Foundation (CFF).

The authors would like to thank the cases and families who participated in this study, the CFF Patient Registry, the University of North Carolina DNA Laboratory, Genome Quebec and McGill University Innovation Centre and the following for their contributions: manuscript preparation: P. Cornwall; study design: A. Hamosh, R. McWilliams; recruitment: S. Adams, M. Algire, N. Anderson, A. Bowers, J. Breaton, C. Bucur, L. Charnin, M. Christofi, B. Coleman, J. Dunn, B. Elkind, D. Fragolias, J. Hoover-Fong, K. Keenan, P. Miller, S. Norris, R. Rousseau, S. Wood, R. Yung and C. Yurk; phenotyping: N. Anderson, J. Breaton, M. Christofi, D. Frangolias, W. Ip, K. Keenan, R. Rousseau and R. Yung; data entry: J. Dunn, S. Norris and T. Lai; genotyping: K. Boden, R. Darrah, Q. Huang, K. Kanieki, F. Lin, S. Ritter, N. Wang, Y. Wang, C. Weiler, W. Wolf and X. Yuan; analysis: A. Dang, E. Hawbaker, L. Henderson, R. McWilliams, Y. Wang, C. Watson and A. Webel; bioinformatics: E. Crowdy, H. Dang, H. Kelkar, T. Randall and A. Xu.

Contributing North American cystic fibrosis centers and principal investigators: S. Aaron, Ottawa General Hospital, Ottawa, Ontario, Canada; F. Accurso, University of Colorado Health Sciences Center, Aurora, Colorado, USA; J. Acton, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA; R. Ahrens, University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA; G. Aljadeff, Lutheran General Children's Hospital, Park Ridge, Illinois, USA; C. Allard, Centre de Santé et de Services Sociaux de Chicoutimi, Chicoutimi, Quebec, Canada; R. Amaro, University of Texas at Tyler Health Center, Tyler, Texas, USA; R. Anbar, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA; P. Anderson, University of Arkansas, Little Rock, Arkansas, USA; A. Atlas, Morristown Memorial Hospital, Morristown, New Jersey, USA; S. Bell, The Prince Charles Hospital, Brisbane, Queensland, Australia; M. Berdella, St. Vincent's Hospital & Medical Center, New York, New York, USA; J. Biller, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA; H. Black, Asthma & Allergy Specialists, Charlotte, North Carolina, USA; P. Black, Children's Mercy Hospital, Kansas City, Missouri, USA; S. Boas, Children's Asthma Respiratory & Exercise Specialists, Glenview, Illinois, USA; M. Boland, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; D. Borowitz, Women's & Children's Hospital of Buffalo, Buffalo, New York, USA; R. Boswell, University of Tennessee, Memphis, Tennessee, USA; J. Boucher, Centre Hospitalier Régional de Rimouski, Rimouski, Quebec, Canada; C.M. Bowman, Medical University of South Carolina, Charleston, South Carolina, USA; M. Boyle, Johns Hopkins Hospital, Baltimore, Maryland, USA; C. Brown, California Pacific Medical Center, San Francisco, California, USA; D. Brown, Pediatric Pulmonary Associates, Columbia, South Carolina, USA; N. Brown, University of Alberta Hospitals, Edmonton, Alberta, Canada; L.F. Caffey, University of New Mexico, Albuquerque, New Mexico, USA; B. Chatfield, University of Utah, Salt Lake City, Utah, USA; S. Chesrown, University of Florida, Gainesville, Florida, USA; B. Chipps, Sutter Medical Center, Sacramento, California, USA; J.P. Clancy, University of Alabama at Birmingham, Birmingham, Alabama, USA; R. Cohen, Kaiser Permanente, Portland, Oregon, USA; J. Colombo, University of Nebraska Medical Center, Omaha, Nebraska, USA; J. Cronin, Women & Children's Hospital of Buffalo, Buffalo, New York, USA; M. Cruz, St. Mary's Medical Center, West Palm Beach, Florida, USA; J. Cunningham, Cook Children's Medical Center, Fort Worth, Texas, USA; G. Davidson, BC Children's Hospital, Vancouver, British Columbia, Canada; L. Davies, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA; J. DeCelie-Germana, Schneider Children's Hospital, New Hyde Park, New York, USA; A. Devenny, Royal Hospital for Sick Children, Edinburgh, Scotland, UK; E. DiMango, Columbia University Medical Center, New York, New York, USA; D. Doornbos, Via-Christi St. Francis, Wichita, Kansas, USA; A. Dozor, New York Medical College-Westchester Medical Center, Valhalla, New York, USA; J. Dunitz, University of Minnesota, Minneapolis, Minnesota, USA; M. Egan, Yale University School of Medicine, New Haven, Connecticut, USA; J. Eichner, Great Falls Clinic, Great Falls, Montana, USA; T. Ferkol, St. Louis Children's Hospital, St. Louis, Missouri, USA; S. Fiel, Morristown Memorial Hospital, Morristown, New Jersey, USA; P. Flume, Medical University of South Carolina, Charleston, South Carolina, USA; A. Freitag, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada; M. Franco, Miami Children's Hospital, Miami, Florida, USA; D. Froh, University of Virginia Health System, Charlottesville, Virginia, USA; N. Garey, Saint John Regional Hospital, Saint John, New Brunswick, Canada; D. Geller, Nemours Children's Clinic, Orlando, Florida, USA; W. Gershan, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA; R. Gibson, Children's Hospital & Regional Medical Center, Seattle, Washington, USA; R. Giusti, Long Island College Hospital, Brooklyn, New York, USA; J. Gjevre, Royal University Hospital, Saskatoon, Saskatchewan, Canada; M. Gondor, University of South Florida, St. Petersburg, Florida, USA; G. Gong, Phoenix Children's Hospital, Phoenix, Arizona, USA; M. Guill, Medical College of Georgia, Augusta, Georgia, USA; H. Gutierrez, University of Alabama at Birmingham, Birmingham, Alabama, USA; A. Hadeh, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA; K. Hardy, Children's Hospital, Oakland, California, USA; P. Hiatt, Texas Children's Hospital, Houston, Texas, USA; D. Hicks, Children's Hospital of Orange County, Orange, California, USA; B. Holmes, Regina General Hospital, Regina, Saskatchewan, Canada; D. Holsclaw, University of Pennsylvania, Philadelphia, Pennsylvania, USA; P. Holzwarth, St. Vincent Hospital, Green Bay, Wisconsin, USA; R. Honicky, Michigan State University, East Lansing, Michigan, USA; M. Howenstine, Riley Hospital for Children, Indianapolis, Indiana, USA; D. Hughes, IWK Health Centre, Halifax, Nova Scotia, Canada; M. Jackson, Grand River Hospital, Kitchener, Ontario, Canada; P. James, Lutheran Hospital, Fort Wayne, Indiana, USA; A. Jenneret, Hôtel Dieu de Montréal, Montréal, Quebec, Canada; P. Joseph, University of Cincinnati, Cincinnati, Ohio, USA; J. Kanga, University of Kentucky, Lexington, Kentucky, USA; M. Katz, Baylor College of Medicine, Houston, Texas, USA; S. Kent, Victoria General Hospital, Victoria, British Columbia, Canada; W. Kepron, Winnipeg Health Sciences Centre, Winnipeg, Manitoba, Canada; M. Knowles, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; P. Konig, University of Missouri, Columbia, Missouri, USA; M. Konstan, Case Western Reserve University, Cleveland, Ohio, USA; T. Kovesi, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; J. Kramer, Oklahoma Cystic Fibrosis Center, Tulsa, Oklahoma, USA; N. Kraynack, Children's Hospital Medical Center of Akron, Akron, Ohio, USA; V. Kumar, Hôpital Régional de Sudbury Regional Hospital, Sudbury, Ontario, Canada; T. Lahiri, Fletcher Allen Health Care, Burlington, Vermont, USA; C. Landon, Pediatric Diagnostic Center, Ventura, California, USA; L. Lands, Montréal Children's Hospital, Montréal, Quebec, Canada; C. Lapin, Connecticut Children's Medical Center, Hartford, Connecticut, USA; M. Larj, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA; J. Ledbetter, TC Thompson Children's Hospital, Chattanooga, Tennessee, USA; R. Lee, Naval Medical Center, Portsmouth, Virginia, USA; M. Leigh, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; L. Lester, University of Chicago Children's Hospital, Chicago, Illinois, USA; T. Lever, Eastern Maine Medical Center, Bangor, Maine, USA; H. Levy, Children's Hospital Boston, Boston, Massachusetts, USA; A. Lieberthal, Kaiser Permanente Southern California, Panorama City, California, USA; T. Liou, University of Utah, Salt Lake City, Utah, USA; A. Lipton, National Naval Medical Center, Bethesda, Maryland, USA; B. Lyttle, Children's Hospital of Western Ontario, London, Ontario, Canada; B. Lothian, Royal University Hospital, Saskatoon, Saskatchewan, Canada; D. Lougheed, Hotel Dieu Hospital, Kingston, Ontario, Canada; K. Malhotra, Grand River Hospital, Kitchener, Ontario, Canada; J. Marcotte, Hôpital Sante-Justine, Montréal, Quebec, Canada; E. Matouk, Montréal Chest Institute, Montréal, Quebec, Canada; M. McCarthy, Providence Medical Center, Spokane, Washington, USA; S. McColley, Children's Memorial Hospital & Northwestern University, Chicago, Illinois, USA; K. McCoy, Nationwide Children's Hospital, Columbus, Ohio, USA; J. McNamara, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA; R. Michael, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; S. Miller, University of Mississippi Medical Center, Jackson, Mississippi, USA; M. Milot, Centre de Santé et de Services Sociaux de Chicoutimi, Chicoutimi, Quebec, Canada; K. Moffett, West Virginia University, Morgantown, West Virginia, USA; M. Montgomery, Alberta Children's Hospital, Calgary, Alberta, Canada; P. Moore, Vanderbilt University Medical Center, Nashville, Tennessee, USA; W. Morgan, Tucson Cystic Fibrosis Center, Tucson, Arizona, USA; R. Morris, Janeway Children's Health & Rehabilitation, St. John's, Newfoundland and Labrador, Canada; M. Morse, Methodist Children's Hospital, San Antonio, Texas, USA; S. Moskowitz, Children's Hospital & Regional Medical Center, Seattle, Washington, USA; R. Moss, Stanford University Medical Center, Palo Alto, California, USA; P. Murphy, University of Nebraska Medical Center, Omaha, Nebraska, USA; E. Nakielna, St. Paul's Hospital, Vancouver, British Columbia, Canada; S. Nasr, University of Michigan Health System, Ann Arbor, Michigan, USA; L. Nassri, Sparks Regional Medical Center, Fort Smith, Arkansas, USA; E. Naureckas, University of Chicago Hospitals, Chicago, Illinois, USA; D. Nielson, University of California at San Francisco, San Francisco, California, USA; M. Noseworthy, Janeway Children's Health & Rehabilitation, St. John's, Newfoundland and Labrador, Canada; B. Noyes, St. Louis University, St. Louis, Missouri, USA; K. Olivier, Wilford Hall US Air Force Medical Center, San Antonio, Texas, USA; E. Olson, University of Florida, Gainesville, Florida, USA; G. Omlor, Akron Children's Hospital, Akron, Ohio, USA; D. Orenstein, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA; B. O'Sullivan, University of Massachusetts Memorial Health Care, Worcester, Massachusetts, USA; H.W. Parker, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; M. Passero, Brown University Medical School Rhode Island Hospital, Providence, Rhode Island, USA; H. Pasterkamp, Children's Hospital of Winnipeg, Winnipeg, Manitoba, Canada; L. Pedder, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada; E. Perkett, Vanderbilt University Medical Center, Nashville, Tennessee, USA; G. Perry, University of Kansas Medical Center, Kansas City, Kansas, USA; N. Petit, Center Hospitalier Rouyn-Noranda, Rouyn-Noranda, Quebec, Canada; M. Pian, University of California San Diego Children's Hospital, San Diego, California, USA; A. Platzker, Children's Hospital of Los Angeles, Los Angeles, California, USA; C. Prestidge, Children's Medical Center of Dallas, Dallas, Texas, USA; A. Price, Children's Hospital of Western Ontario, London, Ontario, Canada; H. Rabin, Foothills Medical Centre, Calgary, Alberta, Canada; P. Radford, Phoenix Children's Hospital, Phoenix, Arizona, USA; F. Ratjen, The Hospital for Sick Children, Toronto, Ontario, Canada; W. Regelmann, University of Minnesota, Minneapolis, Minnesota, USA; C. Ren, University of Rochester Medical Center, Strong Memorial Hospital, Rochester, New York, USA; G. Retsch-Bogart, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; W. Richards, Memphis Lung Physicians, Southaven, Mississippi, USA; M. Riva, Via-Christi, St. Francis Campus, Wichita, Kansas, USA; L. Rivard, Centre Unversitaire de Santé de L'estrie, Sherbrooke, Quebec, Canada; D. Roberts, Providence Medical Center, Anchorage, Alaska, USA; M. Rock, University of Wisconsin Hospital, Madison, Wisconsin, USA; J. Rosen, Albany Medical College, Albany, New York, USA; J. Royall, Children's Hospital of Oklahoma, Oklahoma City, Oklahoma, USA; R. Rubenstein, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; F. Ruiz, University of Mississippi Medical Center, Jackson, Mississippi, USA; T. Scanlin, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; M. Schechter, Emory University, Atlanta, Georgia, USA; H.J. Schmidt, Virginia Commonwealth University, Richmond, Virginia, USA; M. Schwartzman, Joe DiMaggio Children's Hospital, Hollywood, Florida, USA; P. Scott, Georgia Pediatric Pulmonology Associates, PC, Atlanta, Georgia, USA; G. Shay, Kaiser Permanente Medical Center, Oakland, California, USA; R. Simon, University of Michigan Health System, East Lansing, Michigan, USA; P. Smith, Long Island College Hospital, Brooklyn, New York, USA; M. Solomon, The Hospital for Sick Children, Toronto, Ontario, Canada; T. Spencer, Children's Hospital of Boston, Boston, Massachusetts, USA; A. Stecenko, Emory University, Atlanta, Georgia, USA; D. Stokes, University of Tennessee, Memphis, Tennessee, USA; B. 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Authors and Affiliations

1. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
   Fred A Wright, Ethan M Lange, Seunggeun Lee, Gregory M Mayhew, Wei Sun & Fei Zou
2. Child Health Evaluative Sciences, the Hospital for Sick Children, Toronto, Ontario, Canada
   Lisa J Strug, Andreea Cojocaru, Mary Corey, Weili Li & Chelsea Taylor
3. Dalla Lana School of Public Health, the University of Toronto, Toronto, Ontario, Canada
   Lisa J Strug & Lei Sun
4. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
   Vishal K Doshi, Kathleen M Naughton & Garry R Cutting
5. Cystic Fibrosis-Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
   Clayton W Commander, Rhonda G Pace, Jaclyn R Stonebraker, Wanda K O'Neal & Michael R Knowles
6. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
   Scott M Blackman, J Michael Collaco, Deanna Green & Garry R Cutting
7. Department of Medicine, Centre de recherche, Centre Hospitalier de I'Université de Montréal, Montréal, Quebec, Canada
   Yves Berthiaume
8. Department of Human Genetics, Emory University, Atlanta, Georgia, USA
   David Cutler
9. Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada
   Ruslan Dorfman, Johanna M Rommens & Julian Zielenski
10. The Center for Health Research, Oregon Clinical Translational Research Institute, Portland, Oregon, USA
    Katrina Goddard
11. Southwest Foundation for Biomedical Research, San Antonio, Texas, USA
    Jack W Kent Jr & John Blangero
12. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    Ethan M Lange & Wei Sun
13. Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    Jingchun Luo
14. James Hogg Research Centre, Providence Heart + Lung Institute, The University of British Columbia, Vancouver, British Columbia, Canada
    Peter Paré & Andrew Sandford
15. Department of Molecular Genetics, the University of Toronto, Toronto, Ontario, Canada
    Johanna M Rommens
16. Pediatric Pulmonology, Cystic Fibrosis Center, Naval Medical Center, Portsmouth, Virginia, USA
    Lori L Vanscoy
17. Case Western Reserve University Departments of Pediatrics and Genetics, Cleveland, Ohio, USA
    Mitchell L Drumm
18. Program in Physiology and Experimental Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada
    Peter R Durie
19. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
    Peter R Durie

Authors

1. Fred A Wright
2. Lisa J Strug
3. Vishal K Doshi
4. Clayton W Commander
5. Scott M Blackman
6. Lei Sun
7. Yves Berthiaume
8. David Cutler
9. Andreea Cojocaru
10. J Michael Collaco
11. Mary Corey
12. Ruslan Dorfman
13. Katrina Goddard
14. Deanna Green
15. Jack W Kent Jr
16. Ethan M Lange
17. Seunggeun Lee
18. Weili Li
19. Jingchun Luo
20. Gregory M Mayhew
21. Kathleen M Naughton
22. Rhonda G Pace
23. Peter Paré
24. Johanna M Rommens
25. Andrew Sandford
26. Jaclyn R Stonebraker
27. Wei Sun
28. Chelsea Taylor
29. Lori L Vanscoy
30. Fei Zou
31. John Blangero
32. Julian Zielenski
33. Wanda K O'Neal
34. Mitchell L Drumm
35. Peter R Durie
36. Michael R Knowles
37. Garry R Cutting

Contributions

F.A.W., L.J.S., L.S., D.C., M.C., R.D., L.L.V., W.K.O., M.L.D., P.R.D., M.R.K. and G.R.C. worked on study design. Y.B., A.C., J.M.C., M.C., R.D., D.G., W.L., K.M.N., R.G.P., P.P., J.M.R., A.S., J.R.S., C.T., L.L.V., J.Z., M.L.D., P.R.D., M.R.K. and G.R.C. performed sample collection and phenotyping. F.A.W., C.W.C., S.M.B., D.C., K.G., E.M.L., J.L., R.G.P., J.R.S., F.Z., W.K.O., M.L.D., M.R.K. and G.R.C. performed genotyping and data cleaning. F.A.W., L.J.S., V.D., C.W.C., S.M.B., L.S., A.C., J.M.C., M.C., R.D., K.G., J.W.K., E.M.L., S.L., W.L., G.M.M., J.M.R., W.S., C.T., F.Z. and J.B. performed statistical analysis. F.A.W., L.J.S., V.K.D., L.S., R.D., J.M.R., W.K.O., M.L.D., P.R.D., M.R.K. and G.R.C. wrote the manuscript.

Corresponding authors

Correspondence toMichael R Knowles or Garry R Cutting.

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Competing interests

The authors declare no competing financial interests.

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Wright, F., Strug, L., Doshi, V. et al. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2.Nat Genet 43, 539–546 (2011). https://doi.org/10.1038/ng.838

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• Received: 03 November 2010
• Accepted: 22 April 2011
• Published: 22 May 2011
• Issue date: June 2011
• DOI: https://doi.org/10.1038/ng.838