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

2012; Public Library of Science; Volume: 8; Issue: 12 Linguagem: Inglês

10.1371/journal.pgen.1003098

1553-7404

Dana B. Hancock, María Soler Artigas, Sina A. Gharib, Amanda P. Henry, Ani Manichaikul, Adaikalavan Ramasamy, Daan W. Loth, Medea Imboden, Beate Koch, Wendy L. McArdle, Albert V. Smith, Joanna Smolonska, Anil K. Sood, Wenbo Tang, Jemma B. Wilk, Guangju Zhai, Jing Hua Zhao, Hugues Aschard, Kristin M. Burkart, Ivan Curjuric, Mark 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 Brusselle, Ting-hsu Chen, Guðný Eiríksdóttir, 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 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 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. Stricker, Timothy D. Spector, Nicole Probst‐Hensch, Deborah Jarvis, Marjo‐Riitta Järvelin, Susan R. Heckbert, Vilmundur Guðnason, 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,

Epigenetics and DNA Methylation

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.