Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Jemma B. Wilk, Nick R.G. Shrine, Laura R. Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M. Lopez, Albert Vernon Smith, Susan R. Heckbert, Joanna Smolonska, Wenbo Tang, Daan W. Loth, Ivan Curjuric, Jennie Hui, Michael H. Cho, Jeanne C. Latourelle, Amanda P. Henry, Melinda Aldrich, Per Bakke, Terri H. Beaty, Amy R. BentleyIngrid B. Borecki, Guy G. Brusselle, Kristin M. Burkart, Ting Hsu Chen, David Couper, James D. Crapo, Gail Davies, Josée Dupuis, Nora Franceschini, Amund Gulsvik, Dana B. Hancock, Tamara B. Harris, Albert Hofman, Medea Imboden, Alan L. James, Kay Tee Khaw, Lies Lahousse, Lenore J. Launer, Augusto Litonjua, Yongmei Liu, Kurt K. Lohman, David A. Lomas, Thomas Lumley, Kristin D. Marciante, Wendy L. McArdle, Bernd Meibohm, Alanna C. Morrison, Arthur W. Musk, Richard H. Myers, Kari E. North, Dirkje S. Postma, Bruce M. Psaty, Stephen S. Rich, Fernando Rivadeneira, Thierry Rochat, Jerome I. Rotter, María Soler Artigas, John M. Starr, André G. Uitterlinden, Nicholas J. Wareham, Cisca Wijmenga, Pieter Zanen, Michael A. Province, Edwin K. Silverman, Ian J. Deary, Lyle J. Palmer, Patricia A. Cassano, Vilmundur Gudnason, R. Graham Barr, Ruth J.F. Loos, David P. Strachan, Stephanie J. London, H. Marike Boezen, Nicole Probst-Hensch, Sina A. Gharib, Ian P. Hall, George T. O'Connor, Martin D. Tobin, Bruno H. Stricker

Research output: Contribution to journalArticle

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Abstract

Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-basedcohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV 1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Original languageEnglish
Pages (from-to)622-632
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume186
Issue number7
DOIs
StatePublished - Oct 1 2012

Keywords

  • Chronic obstructive pulmonary disease
  • Genes
  • Single-nucleotide polymorphism

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    Wilk, J. B., Shrine, N. R. G., Loehr, L. R., Zhao, J. H., Manichaikul, A., Lopez, L. M., Smith, A. V., Heckbert, S. R., Smolonska, J., Tang, W., Loth, D. W., Curjuric, I., Hui, J., Cho, M. H., Latourelle, J. C., Henry, A. P., Aldrich, M., Bakke, P., Beaty, T. H., ... Stricker, B. H. (2012). Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. American journal of respiratory and critical care medicine, 186(7), 622-632. https://doi.org/10.1164/rccm.201202-0366OC