Epigenetic predictors of time-varying exposures to childhood adversity and depression

童年逆境和抑郁随时间变化的表观遗传预测因子

• 批准号: 10645726
• 负责人: Erin Cathleen Dunn
• 金额: $ 22.44万
• 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: 2023-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645726
• 关键词: Abbreviations; Adolescence; Adolescent; Adult; Affect; Age; Animal Model; Biological; Biological Factors; Birth; Child; Childhood; DNA Methylation; DNA analysis; Data; Data Set; Development; Epigenetic Process; Ethnic Origin; Exposure to; Family; Financial Hardship; Functional disorder; Future; Grant; Household; Human; Life; Life Cycle Stages; Life Experience; Link; Long-Term Effects; Longitudinal Studies; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Mentally Disabled Persons; Meta-Analysis; Methodology; Methylation; Modification; Outcome; Parents; Participant; Pathway interactions; Patient Self-Report; Persons; Population; Population Heterogeneity; Poverty; Prevention; Psyche structure; Psychopathology; Reporting; Research; Research Project Grants; Risk; Sum; Testing; Time; Trauma; Weight; Youth; biomarker identification; burden of illness; child depression; childhood adversity; cohort; cost; depressive symptoms; early life exposure; emerging adult; emotional abuse; epigenetic marker; epigenome; epigenome-wide association studies; high risk; implementation framework; indexing; maltreatment; maternal depression; methylation pattern; novel; novel marker; phenotypic data; population based; programs; prospective; research study; response; risk prediction; socioeconomics; statistics; stressor; study population; tool

ABSTRACT: Depression is one of the most common, costly, and disabling mental disorders and is on track to be the leading cause of disease burden worldwide by 2030. Exposure to adversity during childhood, such as abuse, trauma, poverty, or family disruption, can have profound effects on mental health, more than doubling the risk for depression later in life. These effects are particularly deleterious when they occur during sensitive periods, developmental windows when life experiences can exert greater influences on future outcomes. 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 childhood adversity and its links to depression. However, the predictive power of single DNAm loci is limited, and, as such, recent studies have begun to create composite DNAm risk scores (abbreviated as MRS). Yet, no studies have determined whether sensitive period effects can be integrated into MRS and the extent to which these MRS of time-varying childhood adversity can predict future depressive outcomes. Here, we propose to develop and implement novel methodologies to incorporate the time-varying effects of childhood adversity into MRS, as well as assess the ability of these MRS to explain and predict adult incident depression. We will analyze data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a longitudinal birth cohort that has collected repeated, prospective measures of childhood adversity from ages 0-11, DNAm data in adolescence (age 15-17), and repeated measures of depression between ages 18-28 (n=1,899). In aim 1, we will develop the methodologies necessary to create MRS of time-varying childhood adversity (denoted MRSADV) and determine the extent to which these MRSADV capture prior exposures to childhood adversity. To this end, we will leverage a unique and independent set of summary statistics from our recent meta-analyses of five different types of time-varying childhood adversity and DNAm, which will be used as independent weights in our MRS calculations. In aim 2, we will determine the extent to which MRSADV explain subsequent risk for incident depression, as well as compare the predictive power of MRSADV to self-reports of prior childhood adversity. In sum, this study will: (1) develop new methodologies that can be leveraged to integrate time-varying measures into MRS studies; (2) identify novel epigenetic biomarkers of childhood adversity that can be used to quantify prior exposures to adversity; and (3) determine the extent to which MRS of childhood adversity predict future psychopathology. These findings will not only provide a novel paradigm for studies of MRS and epigenetic mechanisms but will also identify biomarkers that can predict the lifelong consequences of childhood adversity, which will ultimately help target prevention and treatment efforts to people at higher risk for mental illness. The proposed research will also generate preliminary evidence towards future grants focused on socio-biological factors that link childhood adversity to mental health across the life course.

摘要：抑郁症是最常见、最昂贵、最致残的精神疾病之一， 到2030年成为全球疾病负担的主要原因。童年时期的逆境，如 虐待、创伤、贫困或家庭破裂，都可能对心理健康产生深远影响， 以后患抑郁症的风险。当这些影响发生在敏感期时， 在这一时期，生活经历对未来的结果产生更大的影响。 尽管这种脆弱性增加的生物学机制仍然未知，DNA甲基化 （DNAm）-一种表观遗传修饰-已经成为解释长期遗传缺陷的主要候选人。 童年逆境的影响及其与抑郁症的联系。然而，单个DNAm基因座的预测能力是 因此，最近的研究已经开始创建复合DNA风险评分（缩写为MRS）。 然而，还没有研究确定敏感期效应是否可以整合到MRS中，以及 这些随时间变化的童年逆境的MRS可以预测未来的抑郁结果。这里我们 建议开发和实施新的方法，以纳入儿童期随时间变化的影响， 将逆境转化为MRS，以及评估这些MRS解释和预测成人抑郁事件的能力。 我们将分析来自雅芳父母和孩子纵向研究（ALSPAC）的数据， 一个队列收集了0-11岁儿童逆境的重复前瞻性测量数据， 在青春期（15-17岁），并重复测量抑郁症之间的年龄18-28（n= 1，899）。在目标1中， 我们将开发必要的方法来创建随时间变化的童年逆境的MRS（表示为 MRSADV），并确定这些MRSADV捕获儿童期逆境的程度。到 为此，我们将利用最近荟萃分析中的一组独特而独立的汇总统计数据 五种不同类型的随时间变化的童年逆境和DNAm，这将被用作独立的 在我们的MRS计算中的权重。在目标2中，我们将确定MRSADV在多大程度上解释随后的 事件抑郁症的风险，以及比较MRSADV的预测能力，以自我报告的先前 童年的不幸总之，本研究将：（1）开发新的方法，可以利用集成 随时间变化的措施到MRS研究;（2）确定新的表观遗传生物标志物的儿童逆境， 可以用来量化先前暴露于逆境;（3）确定儿童MRS的程度 逆境预示着未来的精神病理学这些发现不仅将为研究提供新的范式， MRS和表观遗传机制，但也将确定生物标志物，可以预测终身后果， 儿童时期的逆境，这将最终有助于针对高危人群开展预防和治疗工作。 精神疾病拟议的研究还将为未来的赠款提供初步证据 侧重于将童年逆境与整个生命过程中的心理健康联系起来的社会生物因素。