A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry

BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.

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.

Trial registration: ClinicalTrials.gov NCT00292552 NCT00608764.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Continental Ancestry Group / genetics*
  • Bronchodilator Agents / pharmacology
  • Chromosomes, Human, Pair 15 / genetics
  • Chromosomes, Human, Pair 4 / genetics
  • Cohort Studies
  • European Continental Ancestry Group / genetics*
  • Female
  • Forced Expiratory Volume
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome, Human
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Risk Factors
  • Smoking / genetics*
  • Spirometry

Substances

  • Bronchodilator Agents

Associated data

  • ClinicalTrials.gov/NCT00292552
  • ClinicalTrials.gov/NCT00608764