# Polygenic prediction of cardiorespiratory fitness in the Trøndelag health study (HUNT)

## TL;DR

This study created a genetic score to predict cardiorespiratory fitness and found it can help identify people at lower risk of heart disease and early death.

## Contribution

The study introduces the first polygenic score for cardiorespiratory fitness using gold-standard measurements and multiple independent cohorts.

## Key findings

- The CRF polygenic score (CRFPGS) showed a 1.55 mL·kg−1·min−1 difference in fitness levels between the lowest and highest genetic risk groups.
- High CRFPGS was linked to reduced risks of cardiovascular disease, heart attack, hypertension, and all-cause mortality.
- In women, the CRFPGS was associated with lower risks of heart failure and hypertrophic cardiomyopathy.

## Abstract

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. Effect estimates from a genome-wide association study on directly measured CRF in the Trøndelag Health Study (HUNT; n = 4525) 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). The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. There was a difference 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. Additionally, in women, we observed that the CRFPGS predisposed to lower risk of heart failure and hypertrophic cardiomyopathy. We developed the first PGS for CRF using gold standard phenotypes and multiple independent cohorts. Genetic susceptibility to high CRF may have a clinically meaningful impact on the phenotype. The CRFPGS was better to identify individuals with slightly higher lifelong levels of CRF, which appears to protect against cardiovascular morbidity and mortality.

The online version contains supplementary material available at 10.1038/s41598-025-28894-7.