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

产前酒精暴露的敏感期：DNA 甲基化和随后心理健康的纵向研究

• 批准号: 10573715
• 负责人: Erin Cathleen Dunn
• 金额: $ 19.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573715
• 关键词: Address; Adolescence; Adolescent; Affect; Age; Age Years; Animals; Applications Grants; Behavioral; Biological; Biological Factors; Birth; Brain; Child; Childhood; Cognitive; Cognitive deficits; Conceptions; Cross-Sectional Studies; DNA Methylation; Data; Development; Environmental Risk Factor; Epigenetic Process; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Future; General Population; Generations; Genetic; Growth; Health; Heterogeneity; Human; Individual; Intervention; Knowledge; Life Cycle Stages; Link; Long-Term Effects; Longevity; Longitudinal Studies; Measurable; Measures; Mediating; Mediation; Mendelian randomization; Mental Depression; Mental Health; Mental disorders; Methods; Modeling; Modification; Outcome; Parents; Pathway interactions; Pattern; Personal Satisfaction; Persons; Population; Predisposition; Pregnancy; Prevention; Psyche structure; Reporting; Research; Research Project Grants; Residual state; Risk; Role; Sampling; Shapes; Signal Transduction; Structure; Symptoms; Testing; Therapeutic; Time; Youth; adverse outcome; alcohol exposure; alcohol measurement; cohort; depressive symptoms; disorder risk; drinking; early life exposure; epigenome; experience; falls; genetic risk factor; genome-wide; high risk; human data; improved; methylation pattern; novel; offspring; parental influence; phenotypic data; population based; prenatal exposure; programs; prospective; research study; therapeutic target

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.

摘要：产前酒精暴露（PAE）会导致各种认知，行为和健康缺陷 落在胎儿酒精谱系障碍（FASD）的伞下。 FASD估计会影响2-7％ 美国的儿童和全球23％。重要的是，患有FASD的人的心理率要高得多 健康问题比普通人群。特别是，多达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。虽然生物学 这种增加脆弱性的机制仍然未知，DNA甲基化（DNAM） - 一种类型 表观遗传修饰 - 已成为解释PAE及其长期影响的主要候选人 链接到抑郁症。但是，大多数人类对PAE及其对DNAM和抑郁症的影响的研究是跨的 截面，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的时间在多大程度上影响童年时期的DNA和抑郁症状 和青少年，并评估DNAM在介导PAE和增加之间的联系中的作用 抑郁症风险。我们将分析来自父母和子女的Avon纵向研究（ALSPAC）的数据， 反复收集的纵向出生队列，怀孕期间对PAE的前瞻性措施，DNAM和 遗传数据和抑郁症的衡量标准从4至16.5岁开始收集。我们将复制发现 在R（genr）中，一个纵向出生队列，与儿童的ALSPAC相似的指标随后 17年。在AIM 1中，我们将评估PAE时机影响父母报告的孩子的程度 抑郁症状轨迹从4至16.5岁。轨迹将使用生长混合物来表征 使用结构化残差进行建模，这是我们以前用来识别六类抑郁症的方法 ALSPAC中的轨迹。因果关系将通过孟德尔随机化和负面测试 控制分析（即怀孕时伴侣饮酒）。在AIM 2中，我们将确定出生时DNAN模式 受PAE时间的影响，并确定这些DNAM介导的程度，或 部分解释了使用统计调解的PAE和抑郁症状轨迹之间的关系 方法。两者的目标都利用了我们先前使用的两阶段结构化生活课程建模方法 当早年暴露对DNA和抑郁症有更大影响时，团队确定年龄段。总而 这项研究将确定：（1）PAE对抑郁症状和DNAM具有更大影响的时期； （2） PAE在儿童期和青少年驱动的抑郁症的特定模式； （3）表观遗传改变 将PAE链接到抑郁症。这些发现将重点介绍发展的窗户和生物学机制 可以针对降低FASD患者抑郁症风险的干预措施，并最大化其 福利。拟议的研究还将为未来的赠款申请提供初步证据 专注于将PAE与整个生活过程中的心理健康联系起来的社会生物学因素。