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

基本信息

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
项目类别：
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

项目摘要

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，昂贵和致残的精神障碍之一，并有望到2030年成为全球疾病的主要原因。虐待，创伤，贫困或家庭破坏会对心理健康产生深远的影响，增加了一倍以上以后生活的抑郁症风险。当这些效果在敏感期间发生时尤其被删除时期，生活经历的发展窗口可以对未来结果产生更大的影响。尽管这种增加脆弱性的生物学机制仍然未知，但DNA甲基化（DNAM） - 一种表观遗传修饰 - 已成为解释长期解释的主要候选人儿童广告及其与抑郁的联系的影响。但是，单DNAM基因座的预测能力是有限，因此，最近的研究已经开始创造复合DNAM风险评分（缩写为MRS）。然而，尚无研究确定是否可以将敏感的时期效应整合到MRS和这些时变儿童广告的太太可以预测未来的抑郁症状。在这里，我们提出开发和实施新方法以纳入童年的时变作用的建议对MRS的逆境以及评估这些MRS解释和预测成人事件抑郁症的能力。我们将分析来自父母和孩子的雅芳纵向研究（ALSPAC）的数据，纵向出生反复收集的队列，从0-11岁的童年广告措施，DNAM数据在青少年（15-17岁）中，以及18-28岁之间的抑郁症措施（n = 1,899）。在AIM 1中，我们将开发创建随时间变化的童年冒险太太的方法（表示 MRSADV）并确定这些MRSADV在多大程度上捕获了对儿童广告的事先暴露。到这一目的，我们将利用我们最近的荟萃分析的独特而独立的摘要统计数据在五种不同类型的时变儿童广告和DNAM中，它们将被用作独立我们的MRS计算中的权重。在AIM 2中，我们将确定MRSADV解释后续序列的程度发生抑郁症的风险，并比较MRSADV的预测能力与先验的自我报告童年广告。总而言之，这项研究将：（1）开发可利用的新方法以整合随着时间变化的措施，将MRS研究; （2）确定儿童期广告的新型表观遗传生物标志物可用于量化事先对广告的曝光；（3）确定童年MRS的程度逆境预测未来的心理病理学。这些发现不仅会为研究提供新颖的范式 MRS和表观遗传机制，但还将确定可以预测终身后果的生物标志物童年广告，最终将有助于针对较高风险的人的预防和治疗工作用于精神疾病。拟议的研究还将为未来赠款提供初步证据专注于将儿童广告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。