TY - JOUR
T1 - Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects
AU - COPDGene Investigators
AU - International COPD Genetics Network
AU - National Emphysema Treatment Trial Genetics
AU - Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points
AU - Busch, Robert
AU - Hobbs, Brian D.
AU - Zhou, Jin
AU - Castaldi, Peter J
AU - McGeachie, Michael J.
AU - Hardin, Megan E
AU - Hawrylkiewicz, Iwona
AU - Sliwinski, Pawel
AU - Yim, Jae Joon
AU - Kim, Woo Jin
AU - Kim, Deog Kyeom
AU - Agusti, Alvar
AU - Make, Barry J
AU - Crapo, James D
AU - Calverley, Peter M
AU - Donner, Claudio F.
AU - Lomas, David A.
AU - Wouters, Emiel Fm
AU - Vestbo, Jorgen
AU - Tal-Singer, Ruth
AU - Bakke, Per
AU - Gulsvik, Amund
AU - Litonjua, Augusto A.
AU - Sparrow, David
AU - Pare, Peter D
AU - Levy, Robert D.
AU - Rennard, Stephen I
AU - Beaty, Terri H
AU - Hokanson, John E.
AU - Silverman, Edwin K
AU - Cho, Michael H
PY - 2017/7/1
Y1 - 2017/7/1
N2 - The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.2831028) and PPP4R4/SERPINA1 (P = 1.0131028) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, z0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.
AB - The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.2831028) and PPP4R4/SERPINA1 (P = 1.0131028) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, z0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.
KW - Chronic obstructive pulmonary disease
KW - Genetic epidemiology
KW - Genetic risk factors; alpha-1 antitrypsin
KW - Genetic risk score
UR - http://www.scopus.com/inward/record.url?scp=85021733485&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2016-0331OC
DO - 10.1165/rcmb.2016-0331OC
M3 - Article
AN - SCOPUS:85021733485
SN - 1044-1549
VL - 57
SP - 35
EP - 46
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 1
ER -