Guo Jia, Riley Kylie W, Durham Teresa, Margolis Amy E, Wang Shuang, Perera Frederica, Herbstman Julie B
Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States.
Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States.
Front Genet. 2022 Mar 31;13:871820. doi: 10.3389/fgene.2022.871820. eCollection 2022.
Prenatal environmental exposures have been associated with children's cognitive, behavioral, and mental health problems, and alterations in DNA methylation have been hypothesized as an underlying biological mechanism. However, when testing this hypothesis, it is often difficult to overcome the problem of multiple comparisons in statistical testing when evaluating a large number of developmental outcomes and DNA methylation sites as potential mediators. The objective of this study is to implement a 'meet-in-the-middle' approach with a sequential roadmap to address this concern. In the Columbia Center for Children's Environmental Health birth cohort study, we implemented a 5-step sequential process for identifying CpG sites that mediate associations between prenatal environmental exposures and cognitive, behavioral, and mental health problems as measured by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and the Child Behavior Checklist (CBCL). These steps include 1) the identification of biological pathways that are relevant to each outcome of interest; 2) selection of a set of genes and CpGs on genes that are significantly associated with the outcomes; 3) identification of exposures that are significantly associated with selected CpGs; 4) examination of exposure-outcome relationships among those where significant CpGs were identified; and 5) mediation analysis of the selected exposures and corresponding outcomes. In this study, we considered a spectrum of environmental exposure classes including environmental phenols, pesticides, phthalates, flame retardants and air pollutants. Among all considered exposures and outcomes, we found one CpG site (cg27510182) on gene (DAB1) that potentially mediates the effect of exposure to PAH on CBCL social problems at children aged 7. This 'meet-in-the-middle' approach attenuates concerns regarding multiple comparisons by focusing on genes and pathways that are biologically relevant for the hypothesis.
产前环境暴露与儿童的认知、行为和心理健康问题有关，DNA甲基化改变被认为是潜在的生物学机制。然而，在检验这一假设时，在评估大量发育结果和作为潜在中介的DNA甲基化位点时，往往难以克服统计检验中的多重比较问题。本研究的目的是采用一种“中间相遇”的方法，并制定一个循序渐进的路线图来解决这一问题。在哥伦比亚儿童环境健康中心出生队列研究中，我们实施了一个五步循序渐进的过程，以识别介导产前环境暴露与认知、行为和心理健康问题之间关联的CpG位点，这些问题通过韦氏儿童智力量表第四版（WISC-IV）和儿童行为清单（CBCL）进行测量。这些步骤包括：1）识别与每个感兴趣的结果相关的生物学途径；2）选择一组与结果显著相关的基因和基因上的CpG；3）识别与所选CpG显著相关的暴露；4）检查在识别出显著CpG的那些暴露与结果之间的关系；5）对所选暴露和相应结果进行中介分析。在本研究中，我们考虑了一系列环境暴露类别，包括环境酚类、农药、邻苯二甲酸盐、阻燃剂和空气污染物。在所有考虑的暴露和结果中，我们在基因（DAB1）上发现了一个CpG位点（cg27510182），它可能介导7岁儿童接触多环芳烃对CBCL社会问题的影响。这种“中间相遇”的方法通过关注与假设生物学相关的基因和途径，减轻了对多重比较的担忧。
