Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?

Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (<i>N</i> = 7,431) and validation (<i>N</i> = 4,307) samples. Using paired genetic-methylation data (<i>N</i> = 4,307), gene–environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, <i>PhenoAge</i> and <i>GrimAge</i>. In the validation sample, PGS explained ~1.4% (<i>P</i> = 1 × 10⁻¹⁴), ~0.6% (<i>P</i> = 2 × 10⁻⁷), and ~8.7% (<i>P</i> = 7 × 10⁻⁸⁷) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (<i>P</i> &lt; 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with <i>PhenoAge</i> and <i>GrimAge</i>, except for alcohol consumption with <i>PhenoAge</i>. There was weak evidence that the association of smoking with <i>GrimAge</i> was attenuated in participants genetically predisposed to smoking (interaction term: −0.022, standard error [SE] = 0.012, <i>P</i> = 0.058) and that the association of alcohol consumption with <i>PhenoAge</i> was attenuated in those genetically predisposed to drink alcohol (interaction term: −0.030, SE = 0.015, <i>P</i> = 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.

已有研究表明，与生活方式相关的表型具有可遗传性，且与DNA甲基化（DNA methylation）存在关联。本研究旨在探究吸烟、饮酒与高体重指数（body mass index, BMI）相关的遗传易感性，是否会调控上述生活方式表型对血液DNA甲基化的影响。
本研究利用训练集（样本量N=7431）与验证集（样本量N=4307），计算多基因评分（polygenic scores, PGS）以量化上述表型的遗传易感性。本研究利用配对的遗传-甲基化数据（样本量N=4307），采用线性混合效应模型评估基因-环境交互作用（即多基因评分×生活方式），结局指标包括：①与吸烟（1061个CpG位点）、饮酒（459个CpG位点）及BMI（85个CpG位点）显著相关的位点甲基化水平；②两项表观遗传衰老（epigenetic ageing）指标：PhenoAge与GrimAge。
在验证集中，多基因评分分别可解释吸烟始发、饮酒及BMI的表型变异约1.4%（P=1×10⁻¹⁴）、0.6%（P=2×10⁻⁷）及8.7%（P=7×10⁻⁸⁷）。针对吸烟、饮酒及BMI，分别在61个、14个及7个CpG位点观察到名义上显著的交互作用（P<0.05）。有充分证据表明，除饮酒与PhenoAge的关联外，所有生活方式相关表型均与PhenoAge及GrimAge呈正相关。有微弱证据显示，在具有吸烟遗传易感性的受试者中，吸烟与GrimAge的关联有所减弱（交互项系数：-0.022，标准误（standard error, SE）=0.012，P=0.058）；而在具有饮酒遗传易感性的受试者中，饮酒与PhenoAge的关联同样有所减弱（交互项系数：-0.030，SE=0.015，P=0.041）。
综上，不健康生活方式的遗传易感性并未显著调控实际生活方式行为与血液DNA甲基化之间的关联。本研究观察到表观遗传衰老指标存在潜在关联，需在后续研究中进行重复验证。