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

Abstract

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10−8) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10−9 for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log10 odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.

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Figure 1: Histograms of the Consortium lung phenotype for the three cystic fibrosis studies showed similar average phenotypes.
Figure 2: Genome-wide Manhattan plots for the cystic fibrosis Consortium lung function phenotype combining the association evidence from GMS and CGS samples across 570,725 SNPs.
Figure 3: A plot of the association evidence in GMS and CGS p.Phe508del/p.Phe508del individuals in the chromosome 11p13 EHF-APIP region (NCBI build 36, LocusZoom viewer).
Figure 4: Genome-wide linkage scan for the Consortium lung phenotype of 486 sibling pairs in the family based TSS dataset adjusted for sex.
Figure 5: Regional analysis of the QTL on chromosome 20q13.2.

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References

  1. The Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N. Engl. J. Med. 329, 1308–1313 (1993).

  2. Vanscoy, L.L. et al. Heritability of lung disease severity in cystic fibrosis. Am. J. Respir. Crit. Care Med. 175, 1036–1043 (2007).

    Article  CAS  Google Scholar 

  3. Cutting, G.R. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann. NY Acad. Sci 1214, 57–69 (2010).

    Article  CAS  Google Scholar 

  4. Chalmers, J.D., Fleming, G.B., Hill, A.T. & Kilpatrick, D.C. Impact of mannose binding lectin (MBL) insufficiency on the course of cystic fibrosis: a review and meta-analysis. Glycobiology 21, 271–282 (2010).

    Article  Google Scholar 

  5. Corey, M., Edwards, L., Levison, H. & Knowles, M. Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J. Pediatr. 131, 809–814 (1997).

    Article  CAS  Google Scholar 

  6. Schluchter, M.D., Konstan, M.W. & Davis, P.B. Jointly modelling the relationship between survival and pulmonary function in cystic fibrosis patients. Stat. Med. 21, 1271–1287 (2002).

    Article  Google Scholar 

  7. Kulich, M. et al. Disease-specific reference equations for lung function in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 172, 885–891 (2005).

    Article  Google Scholar 

  8. Taylor, C. et al. A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis genetic modifier studies. Pediatr. Pulmonol. published online, doi:10.1002/ppul.21456 (1 April 2011).

  9. Drumm, M.L. et al. Gene modifiers of lung disease in cystic fibrosis. N. Engl. J. Med. 353, 1443–1453 (2005).

    Article  CAS  Google Scholar 

  10. Dorfman, R. et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J. Clin. Invest. 118, 1040–1049 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Li, W. et al. Understanding the population structure of North American patients with cystic fibrosis. Clin. Genet. 79, 136–146 (2010).

    Article  Google Scholar 

  12. Chen, W.M. & Abecasis, G.R. Family-based association tests for genomewide association scans. Am. J. Hum. Genet. 81, 913–926 (2007).

    Article  CAS  Google Scholar 

  13. Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    Article  CAS  Google Scholar 

  14. Li, Y., Ding, J. & Mach Abecasis, G.R. 1.0: rapid haplotype reconstruction and missing genotype inference. American Society of Human Genetics Annual Meeting — 56th Annual Meeting 416 (2006).

  15. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247 (1995).

    Article  CAS  Google Scholar 

  16. Göring, H.H., Terwilliger, J.D. & Blangero, J. Large upward bias in estimation of locus-specific effects from genomewide scans. Am. J. Hum. Genet. 69, 1357–1369 (2001).

    Article  Google Scholar 

  17. Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).

    Google Scholar 

  18. Sun, L., Craiu, R.V., Paterson, A.D. & Bull, S.B. Stratified false discovery control for large-scale hypothesis testing with application to genome-wide association studies. Genet. Epidemiol. 30, 519–530 (2006).

    Article  Google Scholar 

  19. Roeder, K., Bacanu, S.A., Wasserman, L. & Devlin, B. Using linkage genome scans to improve power of association in genome scans. Am. J. Hum. Genet. 78, 243–252 (2006).

    Article  CAS  Google Scholar 

  20. Day, A., Carlson, M.R., Dong, J., O'Connor, B.D. & Nelson, S.F. Celsius: a community resource for Affymetrix microarray data. Genome Biol. 8, R112 (2007).

    Article  Google Scholar 

  21. Day, A. et al. Disease gene characterization through large-scale co-expression analysis. PLoS ONE 4, e8491 (2009).

    Article  Google Scholar 

  22. Cao, G. et al. Cloning of a novel Apaf-1-interacting protein: a potent suppressor of apoptosis and ischemic neuronal cell death. J. Neurosci. 24, 6189–6201 (2004).

    Article  CAS  Google Scholar 

  23. Cho, D.H. et al. Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein. J. Biol. Chem. 279, 39942–39950 (2004).

    Article  CAS  Google Scholar 

  24. Cho, D.H. et al. Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2. Oncogene 26, 2809–2814 (2007).

    Article  CAS  Google Scholar 

  25. Oikawa, T. & Yamada, T. Molecular biology of the Ets family of transcription factors. Gene 303, 11–34 (2008).

    Article  Google Scholar 

  26. Tugores, A. et al. The epithelium-specific ETS protein EHF/ESE-3 is a context-dependent transcriptional repressor downstream of MAPK signaling cascades. J. Biol. Chem. 276, 20397–20406 (2001).

    Article  CAS  Google Scholar 

  27. Kas, K. et al. ESE-3, a novel member of an epithelium-specific ets transcription factor subfamily, demonstrates different target gene specificity from ESE-1. J. Biol. Chem. 275, 2986–2998 (2000).

    Article  CAS  Google Scholar 

  28. Silverman, E.S. et al. Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. Am. J. Respir. Cell Mol. Biol. 27, 697–704 (2002).

    Article  CAS  Google Scholar 

  29. Wu, J. et al. Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation. Cell Res. 18, 649–663 (2008).

    Article  CAS  Google Scholar 

  30. Dezso, Z. et al. A comprehensive functional analysis of tissue specificity of human gene expression. BMC Biol. 6, 49 (2008).

    Article  Google Scholar 

  31. Dibbert, B. et al. Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation. Proc. Natl. Acad. Sci. USA 96, 13330–13335 (1999).

    Article  CAS  Google Scholar 

  32. McKeon, D.J. et al. Prolonged survival of neutrophils from patients with Delta F508 CFTR mutations. Thorax 63, 660–661 (2008).

    Article  CAS  Google Scholar 

  33. Harris, J.F. et al. Bcl-2 sustains increased mucous and epithelial cell numbers in metaplastic airway epithelium. Am. J. Respir. Crit. Care Med. 171, 764–772 (2005).

    Article  Google Scholar 

  34. Butler, A.A. The melanocortin system and energy balance. Peptides 27, 281–290 (2006).

    Article  CAS  Google Scholar 

  35. Lee, Y.S., Poh, L.K. & Loke, K.Y. A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J. Clin. Endocrinol. Metab. 87, 1423–1426 (2002).

    Article  CAS  Google Scholar 

  36. Savastano, D.M. et al. Energy intake and energy expenditure among children with polymorphisms of the melanocortin-3 receptor 1–4. Am. J. Clin. Nutr. 90, 912–920 (2009).

    Article  CAS  Google Scholar 

  37. Dorlöchter, L., Roksund, O., Helgheim, V., Rosendahl, K. & Fluge, G. Resting energy expenditure and lung disease in cystic fibrosis. J. Cyst. Fibros. 1, 131–136 (2002).

    Article  Google Scholar 

  38. McCloskey, M. et al. Energy balance in cystic fibrosis when stable and during a respiratory exacerbation. Clin. Nutr. 23, 1405–1412 (2004).

    Article  Google Scholar 

  39. Getting, S.J. et al. A role for MC3R in modulating lung inflammation. Pulm. Pharmacol. Ther. 21, 866–873 (2008).

    Article  CAS  Google Scholar 

  40. Tikhmyanova, N. & Little, J. CAS proteins in normal and pathological cell growth control. Cell. Mol. Life Sci. 67, 1025–1048 (2010).

    Article  CAS  Google Scholar 

  41. Pugacheva, E.N., Jablonski, S.A., Hartman, T.R., Henske, E.P. & Golemis, E.A. HEF1-dependent aurora A activation induces disassembly of the primary cilium. Cell 129, 1351–1363 (2007).

    Article  CAS  Google Scholar 

  42. Hubert, H.B., Fabsitz, R.R., Feinleib, M. & Gwinn, C. Genetic and environmental influences on pulmonary function in adult twins. Am. Rev. Respir. Dis. 125, 409–415 (1982).

    CAS  PubMed  Google Scholar 

  43. McClearn, G.E., Svartengren, M., Pedersen, N.L., Heller, D.A. & Plomin, R. Genetic and environmental influences on pulmonary function in aging Swedish twins. J. Gerontol. 49, 264–268 (1994).

    Article  CAS  Google Scholar 

  44. Wilk, J.B. et al. A genome-wide association study of pulmonary function measures in the Framingham heart study. PLoS Genet. 5, e1000429 (2009).

    Article  Google Scholar 

  45. Hancock, D.B. et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42, 45–52 (2010).

    Article  CAS  Google Scholar 

  46. Repapi, E. et al. Genome-wide association study identifies five loci associated with lung function. Nat. Genet. 42, 36–44 (2010).

    Article  CAS  Google Scholar 

  47. Pillai, S.G. et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 5, e1000421 (2009).

    Article  Google Scholar 

  48. Cho, M.H. et al. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat. Genet. 42, 200–202 (2010).

    Article  CAS  Google Scholar 

  49. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  50. van Houwelingen, H.C., Arends, L.R. & Stijnen, T. Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat. Med. 21, 589–624 (2002).

    Article  Google Scholar 

  51. Burdick, J.T., Chen, W.M., Abecasis, G.R. & Cheung, V.G. In silico method for inferring genotypes in pedigrees. Nat. Genet. 38, 1002–1004 (2006).

    Article  CAS  Google Scholar 

  52. Wang, K. et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007).

    Article  CAS  Google Scholar 

  53. Sun, W. et al. Integrated study of copy number states and genotype calls using high-density SNP arrays. Nucleic Acids Res. 37, 5365–5377 (2009).

    Article  CAS  Google Scholar 

  54. Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    Article  CAS  Google Scholar 

  55. Almasy, L. & Blangero, J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62, 1198–1211 (1998).

    Article  CAS  Google Scholar 

  56. Storey, J.D. A direct approach to false discovery rates. J. R. Stat. Soc. Series B Stat. Methodol. 64, 479–498 (2002).

    Article  Google Scholar 

  57. Yoo, Y.J., Bull, S.B., Paterson, A.D., Waggott, D. & Sun, L. Were genome-wide linkage studies a waste of time? Exploiting candidate regions within genome-wide association studies. Genet. Epidemiol. 34, 107–118 (2010).

    Article  Google Scholar 

  58. Neter, J., Wasserman, W., & Kutner, M. Applied Linear Regression Models 282 (Richard D. Irwin, Homewood, Illinois, USA, 1989).

  59. Hankinson, J.L., Odencrantz, J.R. & Fedan, K.B. Spirometric reference values from a sample of the general U.S. population. Am. J. Respir. Crit. Care Med. 159, 179–187 (1999).

    Article  CAS  Google Scholar 

  60. Wang, X., Dockery, D.W., Wypij, D., Fay, M.E. & Ferris, B.G. Jr. Pulmonary function between 6 and 18 years of age. Pediatr. Pulmonol. 15, 75–88 (1993).

    Article  Google Scholar 

Download references

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. Sullivan, Marshfield Clinic, Marshfield, Wisconsin, USA; J. Taylor-Cousar, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA; N. Thomas, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; H. Thompson, St. Luke's Cystic Fibrosis Clinic, Boise, Idaho, USA; D. Toder, Children's Hospital of Michigan and Harper University Hospital, Detroit, Michigan, USA; E. Tullis, St.Michael's Hospital, Toronto, Ontario, Canada; N. Turcios, University of Medicine & Dentistry of New Jersey, New Brunswick, New Jersey, USA; R. van Wylick, Hotel Dieu Hospital, Kingston, Ontario, Canada; L. Varlotta, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA; P. Vauthy, Toledo Children's Hospital, Toledo, Ohio, USA; J. Voynow, Duke University, Durham, North Carolina, USA; C. Wainwright, Royal Children's Hospital, Melbourne, Victoria, Australia; P. Walker, St. Vincent's Hospital, New York, New York, USA; W.S. Warren, Hershey Medical Center, Hershey, Pennsylvania, USA; P. Wilcox, St. Paul's Hospital, British Columbia, Canada; R. Wilmott, St. Louis University, St. Louis, Missouri, USA; H. Wojtczak, Naval Medical Center, Poway, California, USA; W. Yee, New England Medical Center, Boston, Massachusetts, USA; C. Zacher, St. Alexius Heart & Lung Cystic Fibrosis Clinic, Bismarck, North Dakota, USA; R. Zanni, Monmouth Medical Center, Long Branch, New Jersey, USA; P. Zeitlin, Johns Hopkins Hospital, Baltimore, Maryland, USA; P. Zuberbuhler, University of Alberta Hospitals, Edmonton, Alberta, Canada.

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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.

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Correspondence to Michael R Knowles or Garry R Cutting.

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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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