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

J.B. Wilk, N.R.G. Shrine, L.R. Loehr, J.H. Zhao, A. Manichaikul, L.M. Lopez, A.V. Smith, S.R. Heckbert, J. Smolonska, W. Tang, D.W. Loth, I. Curjuric, Jennie Hui, M.H. Cho, J.C. Latourelle, A.P. Henry, M. Aldrich, P. Bakke, T.H. Beaty, A.R. BentleyI.B. Borecki, G.G. Brusselle, K.M. Burkart, T.-H. Chen, D. Couper, J.D. Crapo, G. Davies, J. Dupuis, N. Franceschini, A. Gulsvik, D.B. Hancock, T.B. Harris, A. Hofman, M. Imboden, Alan James, K.-T. Khaw, L. Lahousse, L.J. Launer, A. Litonjua, Y. Liu, K.K. Lohman, D.A. Lomas, T. Lumley, K.D. Marciante, W.L. Mcardle, B. Meibohm, A.C. Morrison, Arthur Musk, R.H. Myers, K.E. North, D.S. Postma, B.M. Psaty, S.S. Rich, F. Rivadeneira, T. Rochat, J.I. Rotter, M. Soler Artigas, J.M. Starr, A.G. Uitterlinden, N.J. Wareham, C. Wijmenga, P. Zanen, M.A. Province, E.K. Silverman, I.J. Deary, L.J. Palmer, P.A. Cassano, V. Gudnason, R.G. Barr, R.J.F. Loos, D.P. Strachan, S.J. London, H.M. Boezen, N. Probst-Hensch, S.A. Gharib, I.P. Hall, G.T. O'Connor, M.D. Tobin, B.H. Stricker

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Abstract

[Truncated 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-based cohorts 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 FEV1 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....Copyright © 2012 by the American Thoracic Society
Original languageEnglish
Pages (from-to)622-632
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number7
DOIs
Publication statusPublished - 2012

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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