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) 可导致多种认知、行为和健康缺陷 据估计，2-7% 的胎儿患有胎儿酒精谱系障碍 (FASD)。 美国儿童和全球 23% 的儿童患有 FASD，精神障碍的比例要高得多。 尤其是，多达 50% 的 FASD 患者患有比普通人群更严重的健康问题。 抑郁症，使其成为与 PAE 相关的最常见的精神疾病之一。 这种脆弱性增加背后的机制仍然未知，DNA 甲基化 (DNAm) – 一种 表观遗传修饰——已成为解释 PAE 及其长期影响的主要候选者 然而，大多数关于 PAE 及其对 DNAm 和抑郁症影响的人类研究都是交叉的。 部分，因此，没有调查 PAE 的时间是否影响这些关系。 确定 PAE 发生时间对 DNAm 和儿童抑郁症状的影响程度 和青春期，以及评估 DNAm 在介导 PAE 和增加之间的联系中的作用 我们将分析来自雅芳父母和儿童纵向研究 (ALSPAC) 的数据。 纵向出生队列收集了妊娠期间重复的前瞻性 PAE、DNAm 和 从 4 岁到 16.5 岁，几乎每年都会收集遗传数据和抑郁症测量结果。 R 一代 (GenR) 是一个纵向出生队列，其指标与 ASPAC 类似，来自跟踪研究的儿童 在目标 1 中，我们将评估 PAE 发生时间对家长报告的儿童的影响程度。 4 至 16.5 岁的抑郁症状轨迹将使用生长混合物来表征。 使用结构化残差建模，这是我们之前用来识别六类抑郁症的方法 ASPAC 中的轨迹将通过孟德尔随机化和负向检验。 对照分析（即伴侣在怀孕期间饮酒），我们将确定出生时的 DNAm 模式。 受 PAE 时间的影响并确定这些 DNAm 谱介导的程度，或 使用统计中介部分解释 PAE 与抑郁症状轨迹之间的关系 这两个目标都利用了我们之前使用的两阶段结构化生命历程建模方法。 团队确定了早期暴露对 DNAm 和抑郁症影响更大的年龄阶段。 这项研究将确定：(1) PAE 对抑郁症状和 DNAm 影响较大的时期 (2) 由 PAE 驱动的儿童期和青春期抑郁症的特定模式；以及 (3) 表观遗传改变； 这些发现将强调 PAE 与抑郁症之间的联系。 干预措施可以有针对性地降低 FASD 患者的抑郁风险，并最大限度地提高他们的 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。