New genetic determinants of VO2max-level identified by GWAS: The HUNT Study

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Central Norway Regional Health Authority Norwegian Health Association Introduction Cardiovascular disease (CVD) is the leading cause of death worldwide. Several studies have shown that low cardiorespiratory fitness (CRF) is a major risk factor for CVD and is suggested to be a stronger predictor of CVD morbidity and mortality than established cardiovascular risk factors. CRF quantified as maximal oxygen uptake (VO2max) has a strong genetic component, estimated to be ~50%. Unfortunately, current studies on genetic markers for CRF are limited by small sample sizes. In addition, there are few studies on directly measured VO2max, as most of the previous studies are based on estimated CRF. To overcome these limitations, we performed a large-scale systematic screening for genetic variants associated with VO2max aiming to provide awaited insight to this complex trait and discover possible links between VO2max and CVD. Purpose To identify and validate genetic factors associated with VO2max. Methods The genotypes of 70,000 participants from the Trøndelag Health study (HUNT) were imputed providing information on 25 million single-nucleotide polymorphisms (SNPs). We conducted a genome-wide association study (GWAS) including 4,525 participants with directly measured VO2max from the HUNT3 Fitness study. The GWAS was performed using BOLT-LMM, adjusted for age, gender, physical activity, principal components, and genotyping batch. In addition, we ran a GWAS with the same covariates except physical activity. Further, gender specific analyses were conducted. For validation, similar analyses were performed in the United Kingdom Biobank (UKBB). In the UKBB, CRF was assessed through a submaximal bicycle test. The analyses of UKBB included ~60,000 participants and over 90 million SNPs. Functional analyses of the GWAS results were examined by functional mapping and annotation (FUMA). Results Two GWAS-significant (p < 5×10-8) SNPs associated with VO2max were identified in the total population, two in the male population, and 24 in the female population in HUNT. Two of the 24 SNPs found in the female population were nominally significant in the UKBB. One of the validated SNPs in the female population is located inside PIK3R5, that is shown to be of importance in cardiac function and CVD. In addition, the functional analyses in the total- and male population revealed candidate SNPs in a gene previously found to be associated with endurance, PPP3CA. Conclusions We have identified 28 novel SNPs associated with VO2max in the HUNT cohort. Two of these SNPs were nominally validated in females in UKBB. One of the validated SNPs resides within a gene previously reported to be related to heart function and CVD. In addition, the functional analyses in the total- and male population revealed candidate SNPs in a gene previously found to be associated with endurance. Further functional analyses using bioinformatic approaches may provide more information on the physiological importance of these findings and their relation to CVD.