Interactions Between Enhanced Polygenic Risk Scores and Lifestyle for Cardiovascular Disease, Diabetes, and Lipid Levels
Year: 2021
Type: article
Abstract: BACKGROUND: Both lifestyle and genetic factors confer risk for cardiovascular diseases, type 2 diabetes, and dyslipidemia. However, the interactions between these 2 groups of risk factors were not comprehensively understood due to previous poor estimation of genetic risk. Here we set out to develop enhanced polygenic risk scores (PRS) and systematically investigate multiplicative and additive interactions between PRS and lifestyle for coronary artery disease, atrial fibrillation, type 2 diabetes, total cholesterol, triglyceride, and LDL-cholesterol. METHODS: Our study included 276 096 unrelated White British participants from the UK Biobank. We investigated several PRS methods (P+T, LDpred, PRS continuous shrinkage, and AnnoPred) and showed that AnnoPred achieved consistently improved prediction accuracy for all 6 diseases/traits. With enhanced PRS and combined lifestyle status categorized by smoking, body mass index, physical activity, and diet, we investigated both multiplicative and additive interactions between PRS and lifestyle using regression models. RESULTS: We observed that healthy lifestyle reduced disease incidence by similar multiplicative magnitude across different PRS groups. The absolute risk reduction from lifestyle adherence was, however, significantly greater in individuals with higher PRS. Specifically, for type 2 diabetes, the absolute risk reduction from lifestyle adherence was 12.4% (95% CI, 10.0%-14.9%) in the top 1% PRS versus 2.8% (95% CI, 2.3%-3.3%) in the bottom PRS decile, leading to a ratio of >4.4. We also observed a significant interaction effect between PRS and lifestyle on triglyceride level. CONCLUSIONS: By leveraging functional annotations, AnnoPred outperforms state-of-the-art methods on quantifying genetic risk through PRS. Our analyses based on enhanced PRS suggest that individuals with high genetic risk may derive similar relative but greater absolute benefit from lifestyle adherence.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Awards: G2266666766, G2560035637, Misspecified Mixed Model Analysis: Theory and Application, New Statistical Methods for High-Dimensional Association Tests with Applications to Large-Scale Genetic Data, G5850737185, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias
OpenAlex ID: W3119797572