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

Dana B. Hancock, María Soler Artigas, Sina A. Gharib, Amanda Henry, Ani Manichaikul, Adaikalavan Ramasamy, Daan W. Loth, Medea Imboden, Beate Koch, Wendy L. McArdle, Albert V. Smith, Joanna Smolonska, Akshay Sood, Wenbo Tang, Jemma B. Wilk, Guangju Zhai, Jing Hua Zhao, Hugues Aschard, Kristin M. Burkart, Ivan CurjuricMark Eijgelsheim, Paul Elliott, Xiangjun Gu, Tamara B. Harris, Christer Janson, Georg Homuth, Pirro G. Hysi, Jason Z. Liu, Laura R. Loehr, Kurt Lohman, Ruth J.F. Loos, Alisa K. Manning, Kristin D. Marciante, Ma'en Obeidat, Dirkje S. Postma, Melinda C. Aldrich, Guy G. Brusselle, Ting hsu Chen, Gudny Eiriksdottir, Nora Franceschini, Joachim Heinrich, Jerome I. Rotter, Cisca Wijmenga, O. Dale Williams, Amy R. Bentley, Albert Hofman, Cathy C. Laurie, Thomas Lumley, Alanna C. Morrison, Bonnie R. Joubert, Fernando Rivadeneira, David J. Couper, Stephen B. Kritchevsky, Yongmei Liu, Matthias Wjst, Louise V. Wain, Judith M. Vonk, André G. Uitterlinden, Thierry Rochat, Stephen S. Rich, Bruce M. Psaty, George T. O'Connor, Kari E. North, Daniel B. Mirel, Bernd Meibohm, Lenore J. Launer, Kay Tee Khaw, Anna Liisa Hartikainen, Christopher J. Hammond, Sven Gläser, Jonathan Marchini, Peter Kraft, Nicholas J. Wareham, Henry Völzke, Bruno H.C. Stricker, Timothy D. Spector, Nicole M. Probst-Hensch, Deborah Jarvis, Marjo Riitta Jarvelin, Susan R. Heckbert, Vilmundur Gudnason, H. Marike Boezen, R. Graham Barr, Patricia A. Cassano, David P. Strachan, Myriam Fornage, Ian P. Hall, Josée Dupuis, Martin D. Tobin, Stephanie J. London

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109 Citations (Scopus)


Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/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 FEV1 and FEV1/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 PJMA=5.00×10-11), HLA-DQB1 and HLA-DQA2 (smallest PJMA=4.35×10-9), and KCNJ2 and SOX9 (smallest PJMA=1.28×10-8) were associated with FEV1/FVC or FEV1 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.

Original languageEnglish
Article numbere1003098
JournalPLoS Genetics
Issue number12
Publication statusPublished - Dec 2012
Externally publishedYes


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