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.

中文翻译：

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心血管疾病、糖尿病和血脂水平增强的多基因风险评分与生活方式之间的相互作用

背景：生活方式和遗传因素都会导致心血管疾病、2 型糖尿病和血脂异常的风险。然而，由于先前对遗传风险的估计不佳，这两组风险因素之间的相互作用并未得到全面了解。在这里，我们着手开发增强的多基因风险评分 (PRS)，并系统地研究 PRS 与生活方式对冠状动脉疾病、心房颤动、2 型糖尿病、总胆固醇、甘油三酯和低密度脂蛋白胆固醇的乘法和加法相互作用。方法：我们的研究包括来自英国生物银行的 276 096 名无关的英国白人参与者。我们研究了几种 PRS 方法（P+T、LDpred、PRS 连续收缩和 AnnoPred），并表明 AnnoPred 对所有 6 种疾病/性状的预测准确度持续提高。通过增强的 PRS 和按吸烟、体重指数、身体活动和饮食分类的综合生活方式状态，我们使用回归模型研究了 PRS 和生活方式之间的乘法和加法相互作用。结果：我们观察到健康的生活方式以相似的乘法幅度降低了疾病发病率跨不同的 PRS 组。然而，在 PRS 较高的个体中，生活方式坚持所带来的绝对风险降低显着更大。具体而言，对于 2 型糖尿病，生活方式依从性导致的绝对风险降低在前 1% PRS 中为 12.4%（95% CI，10.0%–14.9%），而在前 1% PRS 中为 2.8%（95% CI，2.3%–3.3%）。底部 PRS 十分位，导致比率 >4.4。我们还观察到 PRS 和生活方式对甘油三酯水平的显着交互作用。结论：通过利用功能注释，AnnoPred 在通过 PRS 量化遗传风险方面优于最先进的方法。我们基于增强型 PRS 的分析表明，具有高遗传风险的个体可能会从生活方式的坚持中获得相似的相对但更大的绝对益处。