DNA methylation is associated with body mass index (BMI), but it is not clear if methylation scores are biomarkers for extant BMI or predictive of future BMI. Here, we explore the causal nature and predictive utility of DNA methylation measured in peripheral blood with BMI and cardiometabolic traits. Analyses were conducted across the life course using the ARIES cohort of mothers (n = 792) and children (n = 906), for whom DNA methylation and genetic profiles and BMI at multiple time points (3 in children at birth, in childhood and in adolescence; 2 in mothers during pregnancy and in middle age) were available. Genetic and DNA methylation scores for BMI were derived using published associations between BMI and DNA methylation and genotype. Causal relationships between methylation and BMI were assessed using Mendelian randomisation and cross-lagged models. The DNA methylation scores in adult women explained 10% of extant BMI variance. However, less extant variance was explained by scores generated in the same women during pregnancy (2% BMI variance) and in older children (15–17 years; 3% BMI variance). Similarly, little extant variance was explained in younger children (at birth and at 7 years; 1% and 2%, respectively). These associations remained following adjustment for smoking exposure and education levels. The DNA methylation score was found to be a poor predictor of future BMI using linear and cross-lagged models, suggesting that DNA methylation variation does not cause later variation in BMI. However, there was some evidence to suggest that BMI is predictive of later DNA methylation. Mendelian randomisation analyses also support this direction of effect, although evidence is weak. Finally, we find that DNA methylation scores for BMI are associated with extant cardiometabolic traits independently of BMI and genetic score. The age-specific nature of DNA methylation associations with BMI, lack of causal relationship and limited predictive ability of future BMI indicate that DNA methylation is likely influenced by BMI and might more accurately be considered a biomarker of BMI and related outcomes rather than a predictor. Future epigenome-wide association studies may benefit from further examining associations between early DNA methylation and later health outcomes.

中文翻译：

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DNA 甲基化与体重指数的关联：区分预测因子和生物标志物。

DNA 甲基化与体重指数 (BMI) 相关，但尚不清楚甲基化分数是否是现有 BMI 的生物标志物或未来 BMI 的预测。在这里，我们探讨了外周血中 DNA 甲基化与 BMI 和心脏代谢特征的因果关系和预测效用。使用 ARIES 队列的母亲 (n = 792) 和儿童 (n = 906) 进行了整个生命历程的分析，其中包括多个时间点的 DNA 甲基化、遗传图谱和 BMI（3 个儿童在出生时、儿童期和成年后）。青春期；2 例在怀孕期间和中年期间的母亲中）可用。BMI 的遗传和 DNA 甲基化评分是利用已发表的 BMI 与 DNA 甲基化和基因型之间的关联得出的。使用孟德尔随机化和交叉滞后模型评估甲基化和 BMI 之间的因果关系。成年女性的 DNA 甲基化评分解释了现有 BMI 差异的 10%。然而，现有差异较小的原因是同一女性在怀孕期间（2% BMI 差异）和较大儿童（15-17 岁；3% BMI 差异）产生的分数。同样，年龄较小的儿童（出生时和 7 岁时；分别为 1% 和 2%）几乎没有解释现有的差异。在对吸烟暴露和教育水平进行调整后，这些关联仍然存在。使用线性和交叉滞后模型，发现 DNA 甲基化评分对未来 BMI 的预测效果不佳，这表明 DNA 甲基化变化不会导致 BMI 的后续变化。然而，有一些证据表明 BMI 可预测后来的 DNA 甲基化。孟德尔随机化分析也支持这种效应方向，尽管证据薄弱。最后，我们发现 BMI 的 DNA 甲基化评分与现有的心脏代谢特征相关，独立于 BMI 和遗传评分。DNA 甲基化与 BMI 相关的年龄特异性、缺乏因果关系以及对未来 BMI 的预测能力有限表明 DNA 甲基化可能受到 BMI 的影响，并且可能更准确地被视为 BMI 和相关结果的生物标志物，而不是预测因子。未来的全表观基因组关联研究可能会受益于进一步检查早期 DNA 甲基化与后期健康结果之间的关联。