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Polygenic prediction of cardiorespiratory fitness: The HUNT Study
Karsten Øvretveit1,2, Marie Klevjer3,4, Ben M Brumpton1,5
1HUNT Center for Molecular and Clinical Epidemiology (MCE), Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Insights
A new polygenic score for cardiorespiratory fitness (CRF) was developed and validated. A high CRF polygenic score (PGS) is linked to reduced cardiovascular disease risk and mortality, showing similar benefits to high CRF itself.
Area of Science:
- Genetics
- Cardiology
- Public Health
Background:
- Cardiorespiratory fitness (CRF) has a significant genetic basis.
- Low CRF is a major risk factor for cardiovascular morbidity and mortality.
Purpose of the Study:
- Develop and validate a polygenic score (PGS) for CRF (CRFPGS).
- Assess associations between CRFPGS and cardiovascular disease (CVD) and all-cause mortality.
- Hypothesize that CRFPGS offers cardioprotective benefits comparable to the CRF phenotype.
Main Methods:
- Developed multiple PGSs using effect estimates from a genome-wide association study on directly measured CRF (Trøndelag Health Study, HUNT; n=4,525).
- Utilized a Bayesian regression framework with an independent cohort from the UK Biobank (n=65,165) for PGS development.
- Applied the top-performing PGS in the HUNT target cohort (n=82,109), excluding the discovery sample.
Main Results:
- A difference in CRF of 1.55 mL·kg-1·min-1 was observed between the bottom and top deciles of the CRFPGS in the target population.
- A high CRFPGS was associated with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality.
- CRFPGS was also linked to a lower risk of heart failure and hypertrophic cardiomyopathy in women.
Conclusions:
- A PGS for CRF derived from high-quality phenotypes captures clinically relevant variations in CRF.
- The CRFPGS is associated with a reduced risk of cardiovascular morbidity and mortality.
- Challenges in developing and refining PGS include phenotypic heterogeneity in large populations.
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 (CRFPGS) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRFPGS 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 CRFPGS. Moreover, a high CRFPGS demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. We also found that the CRFPGS 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.
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