Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis

A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (N case = 12,550, N control = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) ( N = 458,969), high blood pressure (HBP) (N case = 144,793, N control = 313,761), coronary artery disease (CAD)(N case = 60,801, N control = 123,504), and stroke (N case = 40,585, N control = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.