A Whole-Genome Approach Discovers Novel Genetic and Non-Genetic Variance Components Modulated by Lifestyle for Cardiovascular Health

Both genetic and non-genetic factors can predispose individuals to cardiovascular risk. Finding ways to alter these predispositions is important for cardiovascular disease (CVD) prevention. Here, we use a novel whole-genome framework to estimate genetic and non-genetic effects on--hence their predispositions to--cardiovascular risk and determine whether they vary with respect to lifestyle factors. We performed analyses on the Atherosclerosis Risk in Communities Study (ARIC, N=6,896-7,180) and validated findings using the UK Biobank (UKBB, N=14,076-34,538). Cardiovascular risk was measured using 23 traits in the ARIC and eight traits in the UKBB, such as body mass index (BMI), resting heart rate, white blood cell count and blood pressure; and lifestyle factors included information on physical activity, smoking, alcohol consumption and dietary intake. Physical activity altered both genetic and non-genetic effects on heart rate and BMI, genetic effects on HDL cholesterol level, and non-genetic effects on waist-to-hip ratio. Alcohol consumption altered both genetic and non-genetic effects on BMI, while smoking altered non-genetic effects on heart rate, pulse pressure, and white blood cell count. In addition, saturated fat intake modified genetic effects on BMI, and total daily energy intake modified non-genetic effects on waist-to-hip ratio. These results highlight the relevance of lifestyle changes for CVD prevention. We also stratified individuals according to their genetic predispositions and showed notable differences in the effects of lifestyle on cardiovascular risk across stratified groups, implying the need for individualizing lifestyle changes for CVD prevention. Finally, we showed that neglecting lifestyle modulation of genetic and non-genetic effects will on average reduce SNP heritability estimates of cardiovascular traits by a small yet significant amount, primarily owing to overestimation of residual variance. Thus, current SNP heritability estimates for cardiovascular traits, which commonly do not consider modulating effects of lifestyle covariates, are likely underestimated.