Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

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Author
Hancock, Dana B.
Artigas, María Soler
Gharib, Sina A.
Henry, Amanda
Manichaikul, Ani
Ramasamy, Adaikalavan
Loth, Daan W.
Imboden, Medea
Koch, Beate
McArdle, Wendy L.
Smith, Albert V.
Smolonska, Joanna
Sood, Akshay
Tang, Wenbo
Zhai, Guangju
Burkart, Kristin M.
Curjuric, Ivan
Eijgelsheim, Mark
Elliott, Paul
Gu, Xiangjun
Harris, Tamara B.
Janson, Christer
Homuth, Georg
Hysi, Pirro G.
Loehr, Laura R.
Lohman, Kurt
Loos, Ruth J. F.
Marciante, Kristin D.
Obeidat, Ma'en
Postma, Dirkje S.
Aldrich, Melinda C.
Brusselle, Guy G.
Eiriksdottir, Gudny
Franceschini, Nora
Heinrich, Joachim
Rotter, Jerome I.
Wijmenga, Cisca
Bentley, Amy R.
Laurie, Cathy C.
Lumley, Thomas
Morrison, Alanna C.
Joubert, Bonnie R.
Rivadeneira, Fernando
Couper, David J.
Kritchevsky, Stephen B.
Liu, Yongmei
Wjst, Matthias
Wain, Louise V.
Vonk, Judith M.
Uitterlinden, André G.
Rochat, Thierry
Rich, Stephen S.
Psaty, Bruce M.
O'Connor, George T.
North, Kari E.
Mirel, Daniel B.
Meibohm, Bernd
Launer, Lenore J.
Khaw, Kay-Tee
Hartikainen, Anna-Liisa
Hammond, Christopher J.
Gläser, Sven
Marchini, Jonathan
Wareham, Nicholas J.
Völzke, Henry
Stricker, Bruno H. C.
Spector, Timothy D.
Probst-Hensch, Nicole M.
Jarvis, Deborah
Jarvelin, Marjo-Riitta
Heckbert, Susan R.
Gudnason, Vilmundur
Boezen, H. Marike
Barr, R. Graham
Cassano, Patricia A.
Strachan, David P.
Fornage, Myriam
Hall, Ian P.
Dupuis, Josée
Tobin, Martin D.
London, Stephanie J.
Zhao, Jing Hua
Liu, Jason Z.
Williams, O. Dale
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1371/journal.pgen.1003098Metadata
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Hancock, Dana B., María Soler Artigas, Sina A. Gharib, Amanda Henry, Ani Manichaikul, Adaikalavan Ramasamy, Daan W. Loth, et al. 2012. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genetics 8(12): e1003098.Abstract
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second \((FEV_1)\), and its ratio to forced vital capacity \((FEV_1/FVC)\). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on \(FEV_1\) and \(FEV_1/FVC\) across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest \(P_{JMA} = 5.00×10^{−11})\), HLA-DQB1 and HLA-DQA2 (smallest \(P_{JMA} = 4.35×10^{−9})\), and KCNJ2 and SOX9 (smallest \(P_{JMA} = 1.28×10^{−8})\) were associated with \(FEV_1/FVC\) or \(FEV_1\) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527213/pdf/Terms of Use
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:10612881
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