Sensitive periods for prenatal alcohol exposure: a longitudinal study of DNA methylation and subsequent mental health

摘要：产前酒精暴露（PAE）可导致各种认知、行为和健康缺陷 属于胎儿酒精谱系障碍（FASD）的范畴。据估计，FASD会影响2-7%的 在美国和全世界的23%。重要的是，患有FASD的人有更高的精神疾病发生率。 健康问题比一般人群。特别是，高达50%的FASD患者患有 抑郁症，使其成为与PAE相关的最普遍的精神疾病之一。虽然生物 这种增加的脆弱性的潜在机制仍然未知，DNA甲基化（DNAm）-一种类型的 表观遗传修饰-已成为解释PAE及其 与抑郁症的联系然而，大多数关于PAE及其对DNAm和抑郁症的影响的人类研究都是交叉的， 因此，尚未研究PAE的时间是否影响这些关系。在这里，我们建议 确定PAE发生的时间对儿童期DNAm和抑郁症状的影响程度 以及评估DNAm在介导PAE和增加的 抑郁风险我们将分析来自雅芳父母和孩子纵向研究（ALSPAC）的数据， 纵向出生队列，收集妊娠期间PAE、DNAm和 基因数据，以及从4岁到16.5岁几乎每年收集的抑郁测量。我们会复制 在R代（GenR）中，一个纵向出生队列，其指标与ALSPAC相似，来自儿童， 17年在目标1中，我们将评估PAE发生的时间在多大程度上影响了父母报告的儿童 抑郁症状轨迹从4岁到16.5岁。将使用生长混合物表征轨迹 用结构化残差建模，我们以前用这种方法来识别六类抑郁症， ALSPAC中的轨迹。将通过孟德尔随机化检验因果关系，结果为阴性 对照分析（即，怀孕期间饮酒）。在目标2中，我们将确定出生时的DNA模式， 受PAE发生时间的影响，并决定这些DNAm谱介导的程度，或 部分解释，PAE和抑郁症状轨迹之间的关系，使用统计中介 方法.这两个目标都利用了我们以前使用的两阶段结构化生命过程建模方法。 研究小组确定了早期生活暴露对DNAm和抑郁症有更大影响的年龄段。总之， 本研究将确定：（1）PAE对抑郁症状和DNA m有较大影响的时期;（2） 由PAE驱动的儿童期和青春期抑郁症的特定模式;和（3）表观遗传改变， 把PAE和抑郁联系起来这些发现将突出发展窗口和生物机制， 可以在干预措施中有针对性地降低FASD患者的抑郁风险， well-being.拟议的研究还将为未来的拨款申请提供初步证据 重点关注将PAE与整个生命过程中的心理健康联系起来的社会生物学因素。

ABSTRACT: Prenatal alcohol exposure (PAE) can lead to a variety of cognitive, behavioral, and health deficits falling under the umbrella of fetal alcohol spectrum disorder (FASD). FASD is estimated to affect 2-7% of children in the USA and 23% worldwide. Importantly, people with FASD have much higher rates of mental health problems than the general population. In particular, up to 50% of people with FASD suffer from depression, making it one of the most prevalent mental illnesses linked to PAE. Although the biological mechanisms underlying this increased vulnerability remain unknown, DNA methylation (DNAm) – a type of epigenetic modification – has emerged as a prime candidate to explain the long-term effects of PAE and its links to depression. However, most human studies of PAE and its effects on DNAm and depression are cross- sectional, and thus, have not investigated if the timing of PAE influences these relationships. Here, we propose to determine the extent to which the timing of PAE influences DNAm and depressive symptoms in childhood and adolescence, as well as assess the role of DNAm in mediating the link between PAE and increased depression risk. We will analyze data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a longitudinal birth cohort that collected repeated, prospective measures of PAE during pregnancy, DNAm and genetic data, and measures of depression collected almost yearly from age 4 to 16.5. We will replicate findings in Generation R (GenR), a longitudinal birth cohort with similar metrics to ALSPAC from children followed for 17 years. In Aim 1, we will assess the extent to which the timing of PAE influences parent-reported, child depressive symptom trajectories from age 4 to 16.5. Trajectories will be characterized using growth mixture modeling with structured residuals, a method we previously used to identify six classes of depression trajectories in ALSPAC. Causal relationships will be tested through Mendelian Randomization and negative control analyses (i.e., partner drinking in pregnancy). In Aim 2, we will identify the DNAm patterns at birth that are influenced by the timing of PAE and determine the extent to which these DNAm profiles mediate, or partially explain, the relationship between PAE and depressive symptom trajectories using statistical mediation methods. Both aims leverage a two-stage structured life course modeling approach previously used by our team to identify age periods when early-life exposures have greater effects on DNAm and depression. In sum, this study will identify: (1) periods when PAE has larger effects on depressive symptoms and DNAm; (2) specific patterns of depression in childhood and adolescence driven by PAE; and (3) epigenetic alterations that link PAE to depression. These findings will highlight developmental windows and biological mechanisms that could be targeted in interventions that reduce depression risk among people with FASD and maximize their well-being. The proposed research will also generate preliminary evidence towards future grant applications focused on socio-biological factors that link PAE to mental health across the life course.