Genome-wide Association Study Identifies New Genetic Determinants of Cardiorespiratory Fitness: The HUNT Study.

Low cardiorespiratory fitness (CRF) is a major risk factor for CVD and a stronger predictor of CVD morbidity and mortality than established risk factors. The genetic component of CRF, quantified as peak oxygen uptake (VO2peak), is estimated to be ~60%. Unfortunately, current studies on genetic markers for CRF have been limited by small sample sizes and using estimated CRF. To overcome these limitations, we performed a large-scale systematic screening for genetic variants associated with VO2peak.A genome-wide association study (GWAS) was performed with BOLT-LMM including directly measured VO2peak from 4,525 participants in the HUNT3 Fitness study and 14 million single-nucleotide polymorphisms (SNPs). For validation, similar analyses were performed in the United Kingdom Biobank (UKB), where CRF was assessed through a submaximal bicycle test, including ~60,000 participants and ~ 60 million SNPs. Functional mapping and annotation of the GWAS results was conducted using FUMA.In HUNT, two genome-wide significant SNPs associated with VO2peak were identified in the total population, two in males, and 35 in females. Two SNPs in the female population showed nominally significant association in the UKB. One of the replicated SNPs is located in PIK3R5, shown to be of importance for cardiac function and CVD. Bioinformatic analyses of the total and male population revealed candidate SNPs in PPP3CA, previously associated with CRF.We identified 38 novel SNPs associated with VO2peak in HUNT. Two SNPs were nominally replicated in UKB. Several interesting genes emerged from the functional analyses, among them one previously reported to be associated with CVD and another with CRF.