Exploring shared genetics between maximal oxygen uptake and disease: the HUNT study

Low cardiorespiratory fitness, measured as maximal oxygen uptake (VO_2max), is associated with all-cause mortality and disease-specific morbidity and mortality and is estimated to have a large genetic component (~60%). However, the underlying mechanisms explaining the associations are not known, and no association study has assessed shared genetics between directly measured VO_2max and disease. We hypothesize that identifying the mechanisms explaining how low VO_2max is related to increased disease risk can contribute to prevention and therapy. We used a phenome-wide association study (PheWAS) approach to test for shared genetics. 64 479 participants from the Trøndelag Health Study (HUNT) were included. Genetic variants found to be associated with VO_2max were tested for association with diseases related to the cardiovascular system, diabetes, dementia, mental disorders, cancer, as well as clinical measurements and biomarkers from HUNT. In the total population, three single nucleotide polymorphisms (SNPs) in and near FSHR were found to be associated (false discovery rate (FDR) < 0.05) with serum creatinine levels, and one intronic SNP in RADIL with diabetes type 1 with neurological manifestations. In males, four intronic SNPs in PKNOX2 were found to be associated with endocarditis. None of the association tests in the female population reached overall statistical significance, the associations with the lowest p-values included other cardiac conduction disorders, subdural hemorrhage, and myocarditis. The results might suggest shared genetics between VO_2max and disease. However, further effort should be put into investigating the potential shared genetics between inborn VO_2max and disease in larger cohorts to increase statistical power.