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Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD

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Abstract

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

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Acknowledgments

This project was part of the Gene, Environment Association Studies (GENEVA) Consortium funded by the National Human Genome Research Institute (NHGRI) to enhance communication and collaboration among researchers conducting genome-wide studies of complex diseases. Our group benefited greatly from the work and efforts of the entire consortium, especially the Coordinating Center (directed by B. Weir and C. Laurie of the University of Washington) in data cleaning and preparation for submission to the Database for Genotypes and Phenotypes (dbGaP). Special thanks also to David Levine for additional, technical support. We also acknowledge the leadership of T. Manolio of NHGRI. We would also like to thank Helen Voelker and Kathy Farnell of the LHS Data Coordinating Center, University of Minnesota for assistance with the LHS database. We would also like to thank Corinne Boehm and Jane Romm of the Center for Inherited Disease Research, Johns Hopkins University, for technical support. The principal investigators and senior staff of the clinical and coordinating centers, the NHLBI, and members of the Safety and Data Monitoring Board of the Lung Health Study are as follows: Case Western Reserve University, Cleveland, OH: M.D. Altose, M.D. (Principal Investigator), C.D. Deitz, Ph.D. (Project Coordinator); Henry Ford Hospital, Detroit, MI: M.S. Eichenhorn, M.D. (Principal Investigator), K.J. Braden, A.A.S. (Project Coordinator), R.L. Jentons, M.A.L.L.P. (Project Coordinator); Johns Hopkins University School of Medicine, Baltimore, MD: R.A. Wise, M.D. (Principal Investigator), C.S. Rand, Ph.D. (Co-Principal Investigator), K.A. Schiller (Project Coordinator); Mayo Clinic, Rochester, MN: P.D. Scanlon, M.D. (Principal Investigator), G.M. Caron (Project Coordinator), K.S. Mieras, L.C. Walters; Oregon Health Sciences University, Portland: A.S. Buist, M.D. (Principal Investigator), L.R. Johnson, Ph.D. (LHS Pulmonary Function Coordinator), V.J. Bortz (Project Coordinator); University of Alabama at Birmingham: W.C. Bailey, M.D. (Principal Investigator), L.B. Gerald, Ph.D., M.S.P.H. (Project Coordinator); University of California, Los Angeles: D.P. Tashkin, M.D. (Principal Investigator), I.P. Zuniga (Project Coordinator); University of Manitoba, Winnipeg: N.R. Anthonisen, M.D. (Principal Investigator, Steering Committee Chair), J. Manfreda, M.D. (Co-Principal Investigator), R.P. Murray, Ph.D. (Co-Principal Investigator), S.C. Rempel-Rossum (Project Coordinator); University of Minnesota Coordinating Center, Minneapolis: J.E. Connett, Ph.D. (Principal Investigator), P.L. Enright, M.D., P.G. Lindgren, M.S., P. O’Hara, Ph.D., (LHS Intervention Coordinator), M.A. Skeans, M.S., H.T. Voelker; University of Pittsburgh, Pittsburgh, PA: R.M. Rogers, M.D. (Principal Investigator), M.E. Pusateri (Project Coordinator); University of Utah, Salt Lake City: R.E. Kanner, M.D. (Principal Investigator), G.M. Villegas (Project Coordinator); Safety and Data Monitoring Board: M. Becklake, M.D., B. Burrows, M.D. (deceased), P. Cleary, Ph.D., P. Kimbel, M.D. (Chairperson; deceased), L. Nett, R.N., R.R.T. (former member), J.K. Ockene, Ph.D., R.M. Senior, M.D. (Chairperson), G.L. Snider, M.D., W. Spitzer, M.D. (former member), O.D. Williams, Ph.D.; Morbidity and Mortality Review Board: T.E. Cuddy, M.D., R.S. Fontana, M.D., R.E. Hyatt, M.D., C.T. Lambrew, M.D., B.A. Mason, M.D., D.M. Mintzer, M.D., R.B. Wray, M.D.; National Heart, Lung, and Blood Institute staff, Bethesda, MD: S.S. Hurd, Ph.D. (Former Director, Division of Lung Diseases), J.P. Kiley, Ph.D. (Former Project Officer and Director, Division of Lung Diseases), G. Weinmann, M.D. (Former Project Officer and Director, Airway Biology and Disease Program, DLD), M.C. Wu, Ph.D. (Division of Epidemiology and Clinical Applications). Principal investigators and centers participating in ECLIPSE include: Bulgaria: Y. Ivanov, Pleven; K. Kostov, Sofia. Canada: J. Bourbeau, Montreal; M. Fitzgerald, Vancouver; P. Hernández, Halifax; K. Killian, Hamilton; R. Levy, Vancouver; F. Maltais, Montreal; .D O’Donnell, Kingston. Czech Republic: J. Krepelka, Praha. Denmark: J. Vestbo, Hvidovre. The Netherlands: E. Wouters, Horn. New Zealand: D. Quinn, Wellington. Norway: P. Bakke, Bergen, Slovenia: M. Kosnik, Golnik. Spain: A. Agusti, Jaume Sauleda, Palma de Mallorca. Ukraine: Y. Feschenko, Kiev; V. Gavrisyuk, Kiev; L. Yashina, Kiev. UK: L. Yashina, W. MacNee, Edinburgh; D. Singh, Manchester; J. Wedzicha, London. USA: A. Anzueto, San Antonio, TX; S. Braman, Providence. RI; R. Casaburi, Torrance CA; B. Celli, Boston, MA; G. Giessel, Richmond, VA; M. Gotfried, Phoenix, AZ; G. Greenwald, Rancho Mirage, CA; N. Hanania, Houston, TX; D, Mahler, Lebanon, NH; B. Make, Denver, CO; S. Rennard, Omaha, NE; C. Rochester, New Haven, CT; P. Scanlon, Rochester, MN; D. Schuller, Omaha, NE; F. Sciurba, Pittsburg, PA; A. Sharafkhaneh, Houston, TX; T. Siler, St Charles, MO; E. Silverman, Boston, MA; A. Wanner, Miami, FL; R. Wise, Baltimore, MD; R. ZuWallack, Hartford, CT. Steering Committee: H. Coxson (Canada), C. Crim (GlaxoSmithKline, USA), L. Edwards (GlaxoSmithKline, USA), D. Lomas (UK), W. MacNee (UK), E. Silverman (USA), R. Tal-Singer (Co-chair, GlaxoSmithKline, USA), J. Vestbo (Co-chair, Denmark), J. Yates (GlaxoSmithKline, USA). Scientific Committee: A. Agusti (Spain), P. Calverley (UK), B. Celli (USA), C. Crim (GlaxoSmithKline, USA), B. Miller (GlaxoSmithKline, US), W. MacNee (Chair, UK), S. Rennard (USA), R. Tal-Singer (GlaxoSmithKline, USA), E. Wouters (The Netherlands), J. Yates (GlaxoSmithKline, USA). Data deposition: Data can be obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000335.v1.p1 through dbGaP accession number phs000335.v1.pl. This research was supported by GENEVA (U01HG004738). The Lung Health Study I was supported by contract NIH/N01-HR-46002. Lung tissue validation studies were supported by the NHLBI HL095406-01. KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. This CHS research was supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL 1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. FHS was funded by N01 HC 25195 from NHLBI. ECLIPSE was supported by GlaxoSmithKline. The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. COPACETIC (acronym of COPD Pathology: Addressing Critical gaps, Early Treatment & diagnosis and Innovative Concepts) is funded by the European Union FP7 program, grant agreement number: 201379. GWAS genotyping was performed at the Center for Inhreited Disease Research under the support of NIH GEI grant U01 HG004438.

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All experiments described here comply with the current laws of the country in which they were performed.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Nadia N. Hansel, Nicholas Rafaels, Alla Malinina, Lili Huang, Tanda Murray, Candelaria Vergara, Robert A. Wise, Enid R. Neptune, Rasika A. Mathias & Kathleen C. Barnes

  2. Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Nadia N. Hansel

  3. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Ingo Ruczinski

  4. Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada

    Don D. Sin, Denise Daley, Andrew Sandford, Farzian Aminuddin & Peter D. Paré

  5. Inherited Disease Research Branch, National Human Genome Research Institute, NIH, Baltimore, MD, USA

    Yoonhee Kim

  6. Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    Guo Li

  7. Departments of Medicine, Epidemiology and Health Services, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    Bruce M. Psaty

  8. Department of Pathology and Laboratory Medicine, James Hogg Research Centre, St Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada

    W. Mark Elliott

  9. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Josée Dupuis

  10. Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    George T. O’Connor

  11. The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    Josée Dupuis & George T. O’Connor

  12. Center for Inherited Disease Research (CIDR), Johns Hopkins University, Baltimore, MD, USA

    Kimberly Doheny & Alan F. Scott

  13. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    H. Marike Boezen

  14. Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Dirkje S. Postma

  15. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Joanna Smolonska

  16. Department of Genetics, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    H. Marike Boezen, Dirkje S. Postma & Joanna Smolonska

  17. Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands

    Pieter Zanen & Firdaus A. Mohamed Hoesein

  18. Department of Public Health, Erasmus Medical Centre, Rotterdam, The Netherlands

    Harry J. de Koning

  19. Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA

    Ronald G. Crystal

  20. Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA

    Toshiko Tanaka & Luigi Ferrucci

  21. Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Edwin Silverman & Emily Wan

  22. University of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark

    Jorgen Vestbo

  23. Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    David A. Lomas

  24. Division of Biostatistics, School of Public Health, University of Minnesota, St. Paul, MN, USA

    John Connett

  25. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Terri H. Beaty

  26. The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 3A.62A, Baltimore, MD, 21224, USA

    Kathleen C. Barnes

  27. Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA

    Susan R. Heckbert & Bruce M. Psaty

  28. Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    Susan R. Heckbert

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  1. Nadia N. Hansel
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  2. Ingo Ruczinski
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  3. Nicholas Rafaels
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  4. Don D. Sin
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  5. Denise Daley
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  6. Alla Malinina
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  7. Lili Huang
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  8. Andrew Sandford
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  9. Tanda Murray
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  10. Yoonhee Kim
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  11. Candelaria Vergara
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  12. Susan R. Heckbert
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  13. Bruce M. Psaty
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  14. Guo Li
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  15. W. Mark Elliott
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  16. Farzian Aminuddin
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  17. Josée Dupuis
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  18. George T. O’Connor
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  19. Kimberly Doheny
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  20. Alan F. Scott
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Corresponding author

Correspondence to Kathleen C. Barnes.

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Hansel, N.N., Ruczinski, I., Rafaels, N. et al. Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. Hum Genet 132, 79–90 (2013). https://doi.org/10.1007/s00439-012-1219-6

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  • DOI: https://doi.org/10.1007/s00439-012-1219-6

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