Cardiovascular disease-wide association study to investigate shared genetics with peak oxygen uptake

Abstract

Abstract Introduction Cardiorespiratory fitness, measured as peak oxygen uptake (VO2peak), is a strong predictor of cardiovascular disease (CVD) morbidity and mortality and is estimated to have a large genetic component (∼60%). However, the genetic determinants are yet to be established. Our research group recently identified novel genetic variants associated with directly measured VO2peak. Interestingly, most were specific to females. Looking into genetic pleiotropy between VO2peak and CVD can help elucidate the biological mechanisms explaining the link between this fitness related trait and disease, and potentially identify new therapeutic targets. Purpose The association study aims to investigate if genetic variants found to be associated with VO2peak in women is associated with any cardiovascular disease phenotypes. Methods 34,188 female participants with genotype data from the Trøndelag Health Study (HUNT) were included in this study. ICD-coded hospital data related to cardiovascular disease was collected on each participant and the ICD codes were mapped to Phecodes, resulting in 100 disease-specific phenotypes. 26 single nucleotide polymorphisms (SNPs) previously found to be associated with directly measured VO2peak (p<5e-6) were included in the analyses, all common variants (minor allele frequency ≥1%). Each of the 26 genetic variants were tested for association with the 100 phenotypes using a logistic mixed model as implemented in SAIGE. The analysis was adjusted for birthyear and ten principal components of ancestry. The Benjamini-Hochberg false discovery rate (FDR) procedure controlling the FDR at 0.05 was used to correct for the number of tested SNPs and phenotypes. Results After testing each of the 26 SNPs for association with 100 cardiovascular disease phenotypes, 133 SNP-phenotype associations were nominally significant (p<0.05). The association between rs17066736 and myocarditis had the lowest p-value (1.7e-4). Among the other tested SNP-phenotype pairs were phenotypes related to ischemic heart disease, cardiac conduction disorders, heart failure, cerebrovascular disease, and diseases of arteries and veins. However, when adjusting for multiple testing, none reached overall statistical significance. Conclusions The findings showed no statistically significant associations between genetic variants associated with VO2peak and cardiovascular disease phenotypes in women. The role of inborn VO2peak in prediction of CVD (in women) needs further assessment. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): NTNU biotechnology