Robert Busch, Brian D Hobbs, Jin Zhou, Peter J Castaldi, Michael J McGeachie, Megan E Hardin, Iwona Hawrylkiewicz, Pawel Sliwinski, Jae-Joon Yim, Woo Jin Kim, Deog K Kim, Alvar Agusti, Barry J Make, James D Crapo, Peter M Calverley, Claudio F Donner, David A Lomas, Emiel F Wouters, Jørgen Vestbo, Ruth Tal-Singer, Per Bakke, Amund Gulsvik, Augusto A Litonjua, David Sparrow, Peter D Paré, Robert D Levy, Stephen I Rennard, Terri H Beaty, John Hokanson, Edwin K Silverman, Michael H Cho

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 (SNP) in 2,588 cases (1,803 severe COPD) and 1,782 controls 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 controls. Additionally, 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=1.28x10-8) and PPP4R4/SERPINA1 (p=1.01x10-8) 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 (AUC ~0.6), and accounted for a mean 0.9-1.9% lower FEV1 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.