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

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Lutz, Sharon M.
Young, Kendra
Regan, Elizabeth
Mattheisen, Manuel
Parker, Margaret
Foreman, Marilyn
Make, Barry J.
Jensen, Robert L.
Casaburi, Richard
Lomas, David A.
Bhatt, Surya P.
Bakke, Per
Gulsvik, Amund
Crapo, James D.
Beaty, Terri H.
Hokanson, John E.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1186/s12863-015-0299-4Metadata
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Lutz, S. M., M. H. Cho, K. Young, C. P. Hersh, P. J. Castaldi, M. McDonald, E. Regan, et al. 2015. “A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.” BMC Genetics 16 (1): 138. doi:10.1186/s12863-015-0299-4. http://dx.doi.org/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. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0299-4) contains supplementary material, which is available to authorized users.Other Sources
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