title: Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.
abstract: BACKGROUND
  The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies.
  
  
  METHODS
  We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5 × 10(-8)).
  
  
  RESULTS
  Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10(-14)), FAM13A (p=1·12 × 10(-14)), and HHIP (p=1·57 × 10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10(-9)) and TGFB2 (overall joint meta-analysis p=8·3 × 10(-9)).
  
  
  CONCLUSIONS
  We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD.
  
  
  BACKGROUND
  US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: remhc@channing.harvard.edu.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Merry-Lynn N
authors.initials: ML
authors.lastname: McDonald
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard School of Public Health, Boston, MA, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jody S
authors.initials: JS
authors.lastname: Sylvia
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ziniti
authors.affiliation: Harvard School of Public Health, Boston, MA, USA.
authors.forename: Nan M
authors.initials: NM
authors.lastname: Laird
authors.affiliation: Harvard School of Public Health, Boston, MA, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.affiliation: School of Public Health and School of Medicine, Boston University, Boston, MA, USA; Veterans Administration Boston Healthcare System, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Casaburi
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Mailman School of Public Health, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: National Jewish Health, Denver, CO, USA; Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Regan
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.affiliation: Department of Bioinformatics and Statistics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lutz
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Tanda Murray
authors.initials: TM
authors.lastname: Dudenkov
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Homayoon
authors.initials: H
authors.lastname: Farzadegan
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Hetmanski
authors.affiliation: GlaxoSmithKline Research and Development, King Of Prussia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: University College London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*