Polygenic prediction of cardiorespiratory fitness: The HUNT Study
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Background
Cardiorespiratory fitness (CRF) has a strong genetic component and low CRF is a major risk factor for cardiovascular morbidity and mortality. The purpose of this study was to develop and validate a polygenic score (PGS) for CRF (CRF PGS ) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRF PGS would demonstrate similar cardioprotective benefits as the CRF phenotype.
Methods
Effect estimates from a genome-wide association study on directly measured CRF in the Trøndelag Health Study (HUNT; n = 4 525) were used in a Bayesian regression framework to develop multiple PGSs in an independent cohort from the UK Biobank ( n = 65 165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample ( n = 82 109).
Results
The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. In the target population, we observed a difference in CRF of 1.55 [95% confidence interval: 1.26, 1.84] mL·kg -1 ·min -1 between the bottom and top decile of the CRF PGS . Moreover, a high CRF PGS demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. We also found that the CRF PGS predisposed to lower risk of heart failure and hypertrophic cardiomyopathy in women.
Conclusion
A PGS for CRF derived from gold-standard phenotypes captures small, but potentially clinical meaningful variations in CRF, and is associated with reduced risk of cardiovascular morbidity and mortality. Heterogeneity in CRF phenotyping in large populations remains a challenge to PGS development and refinement.
