Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
Creators: name: Hancock, Dana B.
name: Artigas, Maria Soler
name: Gharib, Sina A.
name: Henry, Amanda
name: Manichaikul, Ani
name: Ramasamy, Adaikalavan
name: Loth, Daan W.
name: Imboden, Medea
name: Koch, Beate
name: McArdle, Wendy L.
name: Smith, Albert V.
name: Smolonska, Joanna
name: Sood, Akshay
name: Tang, Wenbo
name: Wilk, Jemma B.
name: Zhai, Guangju
name: Zhao, Jing Hua
name: Aschard, Hugues
name: Burkart, Kristin Marie
name: Curjuric, Ivan
name: Eijgelsheim, Mark
name: Elliott, Paul
name: Gu, Xiangjun
name: Harris, Tamara B.
name: Janson, Christer
name: Homuth, Georg
name: Hysi, Pirro G.
name: Liu, Jason Z.
name: Loehr, Laura R.
name: Lohman, Kurt
name: Loos, Ruth J. F.
name: Manning, Alisa K.
name: Marciante, Kristin D.
name: Obeidat, Ma’en
name: Postma, Dirkje S.
name: Aldrich, Melinda C.
name: Brusselle, Guy G.
name: Chen, Ting-Hsu
name: Eiriksdottir, Gudny
name: Franceschini, Nora
name: Heinrich, Joachim
name: Rotter, Jerome I.
name: Wijmenga, Cisca
name: Williams, O. Dale
name: Bentley, Amy R.
name: Hofman, Albert
name: Laurie, Cathy C.
name: Lumley, Thomas
name: Morrison, Alanna C.
name: Joubert, Bonnie R.
name: Rivadeneira, Fernando
name: Couper, David J.
name: Kritchevsky, Stephen B.
name: Liu, Yongmei
name: Wjst, Matthias
name: Wain, Louise V.
name: Vonk, Judith M.
name: Uitterlinden, Andre G.
name: Rochat, Thierry
name: Rich, Stephen S.
name: Psaty, Bruce M.
name: O’Connor, George T.
name: North, Kari E.
name: Mirel, Daniel B.
name: Meibohm, Bernd
name: Launer, Lenore J.
name: Khaw, Kay-Tee
name: Hartikainen, Anna-Liisa
name: Hammond, Christopher J.
name: Glaser, Sven
name: Marchini, Jonathan
name: Kraft, Peter
name: Wareham, Nicholas J.
name: Volzke, Henry
name: Stricker, Bruno H. C.
name: Spector, Timothy D.
name: Probst-Hensch, Nicole M.
name: Jarvis, Deborah
name: Jarvelin, Marjo-Riitta
name: Heckbert, Susan R.
name: Gudnason, Vilmundur
name: Boezen, H. Marike
name: Barr, R. Graham
name: Cassano, Patricia A.
name: Strachan, David P.
name: Fornage, Myriam
name: Hall, Ian P.
name: Dupuis, Josee
name: Tobin, Martin D.
name: London, Stephanie J.
Publisher: name: Columbia University
Year: 2012
Subjects: Meta-analysis
Single nucleotide polymorphisms
Lungs
Smoking

description: 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.