title: A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.
abstract: BACKGROUND
  Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532).
  
  
  RESULTS
  Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)).
  
  
  CONCLUSIONS
  In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.
authors.affiliation: Department of Biostatistics, University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, B119 Bldg. 500, W3128, Aurora, CO, 80045, USA. sharon.lutz@ucdenver.edu.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Lutz
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. remhc@channing.harvard.edu.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. kendra.young@ucdenver.edu.
authors.forename: Kendra
authors.initials: K
authors.lastname: Young
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. craig.hersh@channing.harvard.edu.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. repjc@channing.harvard.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. remrm@channing.harvard.edu.
authors.forename: Merry-Lynn
authors.initials: ML
authors.lastname: McDonald
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA. regane@njhealth.org.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Regan
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mm@hum-gen.au.dk.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. redld@channing.harvard.edu.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. mmparker1@gmail.com.
authors.forename: Margaret
authors.initials: M
authors.lastname: Parker
authors.affiliation: Morehouse School of Medicine, Atlanta, GA, USA. mforeman@msm.edu.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Foreman
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA. makeb@njhealth.org.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.affiliation: Division of Pulmonary, Allergy & Critical Care Medicine, LDS Hospital, Salt Lake City, UT, USA. ldrjens1@ihc.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jensen
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. casaburi@ucla.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Casaburi
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, London, UK. d.lomas@ucl.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. spbhatt@uab.edu.
authors.forename: Surya P
authors.initials: SP
authors.lastname: Bhatt
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway. per.bakke@med.uib.no.
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway. amund.gulsvik@med.uib.no.
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA. crapoj@njc.org.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. tbeaty@jhsph.edu.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. nanlaird@gmail.com.
authors.forename: Nan M
authors.initials: NM
authors.lastname: Laird
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. langech2007@gmail.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. John.Hokanson@ucdenver.edu.
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ed.silverman@channing.harvard.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D044383:Black People / Q000235:genetics*; D001993:Bronchodilator Agents / Q000494:pharmacology; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D013147:Spirometry; D044465:White People / Q000235:genetics*; D001741:Black or African American
chemical_list: D001993:Bronchodilator Agents