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

Fred A. Wright, Lisa J. Strug, Vishal K. Doshi, Clayton W. Commander, Scott M. Blackman, Lei Sun, Yves Berthiaume, David Cutler, Andreea Cojocaru, J. Michael Collaco, Mary Corey, Ruslan Dorfman, Katrina Goddard, Deanna Green, Jack W. Kent, Ethan M. Lange, Seunggeun Lee, Weili Li, Jingchun Luo, Gregory M. MayhewKathleen M. Naughton, Rhonda G. Pace, Peter Paré, Johanna M. Rommens, Andrew Sandford, Jaclyn R. Stonebraker, Wei Sun, Chelsea Taylor, Lori L. Vanscoy, Fei Zou, John Blangero, Julian Zielenski, Wanda K. O'Neal, Mitchell L. Drumm, Peter R. Durie, Michael R. Knowles, Garry R. Cutting

    Research output: Contribution to journalArticle

    153 Scopus citations

    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 (log 10 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.

    Original languageEnglish (US)
    Pages (from-to)539-546
    Number of pages8
    JournalNature Genetics
    Volume43
    Issue number6
    DOIs
    StatePublished - Jun 1 2011

    ASJC Scopus subject areas

    • Genetics

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    Wright, F. A., Strug, L. J., Doshi, V. K., Commander, C. W., Blackman, S. M., Sun, L., Berthiaume, Y., Cutler, D., Cojocaru, A., Collaco, J. M., Corey, M., Dorfman, R., Goddard, K., Green, D., Kent, J. W., Lange, E. M., Lee, S., Li, W., Luo, J., ... Cutting, G. R. (2011). Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nature Genetics, 43(6), 539-546. https://doi.org/10.1038/ng.838