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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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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. 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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. 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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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