title: A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes.
  
  
  OBJECTIVE
  To identify genetic determinants of quantitative imaging phenotypes.
  
  
  METHODS
  We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD.
  
  
  RESULTS
  The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes.
  
  
  CONCLUSIONS
  Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD and also identify imaging features associated with previously identified lung function loci.
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hobbs
authors.affiliation: 3 Department of Medicine, College of Physicians and Surgeons, and.|4 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: 5 GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: 6 Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.affiliation: 6 Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.affiliation: 7 Laboratory of Mathematics in Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Raúl
authors.initials: R
authors.lastname: San José Estépar
authors.affiliation: 8 Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.|9 Department of Radiology and.|10 Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors.forename: Edwin J R
authors.initials: EJ
authors.lastname: Van Beek
authors.affiliation: 11 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Harvey O
authors.initials: HO
authors.lastname: Coxson
authors.affiliation: 12 Department of Radiology, National Jewish Health, Denver, Colorado.
authors.forename: David A
authors.initials: DA
authors.lastname: Lynch
authors.affiliation: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.affiliation: 13 Harvard School of Public Health, Boston, Massachusetts; and.
authors.forename: Nan M
authors.initials: NM
authors.lastname: Laird
authors.affiliation: 12 Department of Radiology, National Jewish Health, Denver, Colorado.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: 14 Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000368:Aged; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007091:Image Processing, Computer-Assisted; D035942:Iron Regulatory Protein 2 / Q000235:genetics; D008137:Longitudinal Studies; D008168:Lung / Q000000981:diagnostic imaging*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000000981:diagnostic imaging / Q000235:genetics; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D015843:Serpins / Q000235:genetics; D014057:Tomography, X-Ray Computed; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D035942:Iron Regulatory Protein 2; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D000067759:Receptor for Advanced Glycation End Products; D011978:Receptors, Nicotinic; D015843:Serpins; D025521:Tumor Suppressor Proteins; C000593871:AGER protein, human; C447158:CHRNA5 protein, human; C112352:DLC1 protein, human; C117596:HHIP protein, human; C416370:SERPINA10 protein, human
keywords: airway; chronic obstructive pulmonary disease; emphysema; genetics