Background

The exposome is defined as encompassing all environmental exposures one undergoes from conception onwards. Challenges of the application of this concept to environmental-health association studies include a possibly high false-positive rate.

Objectives

We aimed to reduce the dimension of the exposome using information from DNA methylation as a way to more efficiently characterize the relation between exposome and child body mass index (BMI).

Methods

Among 1,173 mother–child pairs from HELIX cohort, 216 exposures (“whole exposome”) were characterized. BMI and DNA methylation from immune cells of peripheral blood were assessed in children at age 6–10 years. A priori reduction of the methylome to preselect BMI-relevant CpGs was performed using biological pathways. We then implemented a tailored Meet-in-the-Middle approach to identify from these CpGs candidate mediators in the exposome-BMI association, using univariate linear regression models corrected for multiple testing: this allowed to point out exposures most likely to be associated with BMI (“reduced exposome”). Associations of this reduced exposome with BMI were finally tested. The approach was compared to an agnostic exposome-wide association study (ExWAS) ignoring the methylome.

Results

Among the 2284 preselected CpGs (0.6% of the assessed CpGs), 62 were associated with BMI. Four factors (3 postnatal and 1 prenatal) of the exposome were associated with at least one of these CpGs, among which postnatal blood level of copper and PFOS were directly associated with BMI, with respectively positive and negative estimated effects. The agnostic ExWAS identified 18 additional postnatal exposures, including many persistent pollutants, generally unexpectedly associated with decreased BMI.

Discussion

Our approach incorporating a priori information identified fewer significant associations than an agnostic approach. We hypothesize that this smaller number corresponds to a higher specificity (and possibly lower sensitivity), compared to the agnostic approach. Indeed, the latter cannot distinguish causal relations from reverse causation, e.g. for persistent compounds stored in fat, whose circulating level is influenced by BMI.

中文翻译：

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使用甲基化组数据为暴露体-健康关联研究提供信息：用于识别儿童体重指数的环境驱动因素

背景

暴露组被定义为涵盖人们从受孕开始经历的所有环境暴露。将此概念应用于环境-健康关联研究的挑战包括可能的高假阳性率。

目标

我们旨在使用来自 DNA 甲基化的信息来减少暴露体的维度，以此作为更有效地表征暴露体与儿童体重指数 (BMI) 之间关系的方法。

方法

在来自 HELIX 队列的 1,173 对母婴中，表征了 216 次暴露（“整个暴露组”）。在 6-10 岁的儿童中评估了外周血免疫细胞的 BMI 和 DNA 甲基化。使用生物学途径对甲基化组进行先验减少以预选 BMI 相关的 CpG。然后，我们实施了一种量身定制的中间会面方法，从暴露组-BMI 关联中的这些 CpGs 候选介质中识别，使用单变量线性回归模型进行多次测试校正：这允许指出最有可能与 BMI 相关的暴露（“减少的暴露组”）。最终测试了这种减少的暴露组与 BMI 的关联。该方法与忽略甲基化组的不可知暴露组范围关联研究 (ExWAS) 进行了比较。

结果

在 2284 个预选的 CpG（评估 CpG 的 0.6%）中，62 个与 BMI 相关。暴露组的四个因素（3 个产后和 1 个产前）与这些 CpG 中的至少一个相关，其中产后血铜和全氟辛烷磺酸水平与 BMI 直接相关，分别具有正面和负面的估计影响。不可知论者 ExWAS 确定了 18 种额外的产后暴露，包括许多持久性污染物，通常与 BMI 降低意外相关。

讨论

我们结合先验信息的方法比不可知的方法识别出更少的重要关联。我们假设与不可知的方法相比，这个较小的数字对应于更高的特异性（并且可能更低的敏感性）。事实上，后者无法区分因果关系与反向因果关系，例如，对于储存在脂肪中的持久性化合物，其循环水平受 BMI 影响。