Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity

描述（由申请人提供）：社会心理影响涉及影响人类健康的几种最常见疾病（心血管疾病、糖尿病、癌症）的病因学。据推测，这些社会心理影响是通过基于dna的生物学变化介导的，如甲基化改变或端粒磨损。然而，由于这一领域的研究缺乏，许多问题仍然存在：表观遗传和获得性基因组变化在多大程度上在人类的一生中积累？童年的逆境会导致持续到成年的生理变化吗？是否可以根据他们的表观遗传学、基因表达、端粒、染色体不稳定性和/或皮质醇水平谱来确定一个暴露于童年逆境的成年人患疾病的“风险”？为了回答这些问题，我们将研究736对双胞胎，他们在之前的研究中完成了强烈的表型行为评估（完成于2至15年前），并代表两个风险组：(1)经历过童年性虐待极端逆境事件的双胞胎；(2)双胞胎经历了广泛的社会经历。队列1（40-55岁）将包括50对同卵双胞胎的样本，这些双胞胎在童年时期有过不一致的性虐待史，以及50对在童年时期有过（25对）或没有经历过性虐待的同卵双胞胎（25对）。在这个队列中，将测量和比较双胞胎之间的生物学终点包括：(1)使用基于序列的方法进行全基因组甲基化变化的频率和位置；(2)染色体特异性端粒长度；(3)获得性染色体不稳定性的频率；(4)基因表达模式；(4)日基础唾液皮质醇水平。队列2（年龄20-30岁）将由同卵双胞胎（157对）和异卵双胞胎（111对）的标准样本组成，这些双胞胎的行为表型已经在青春期到青年期被仔细确定。从这些双胞胎的研究中获得的数据将为多重逆境对嵌入式生物变化的潜在累积效应提供见解。该队列（先前已收集血液样本并随时可用）的生物学终点包括：(1)使用基于阵列的方法进行全基因组甲基化变化的频率和位置；(2)基因表达模式。总的来说，将观察到的生物终点测量（双胞胎内部和双胞胎之间）的变化与从人类生命的多个阶段收集的表型数据进行比较，将使我们能够推断出观察到的生物标志物差异受童年逆境、成年逆境和/或其他环境压力因素影响的程度。这项研究的数据将导致第一次直接估计表观遗传、端粒长度、获得性染色体不稳定性、基因表达和/或皮质醇水平变化的频率，这些变化是由于童年逆境引起的。

DESCRIPTION (provided by applicant): Psychosocial influences have been implicated in the etiology of several of the most common illnesses impacting human health (cardiovascular disease; diabetes; cancer). It has been hypothesized that these psychosocial effects are mediated through DNA-based biological changes, such as methylation alterations or telomere attrition. However, due to the paucity of research in this area, many questions remain: To what extent do epigenetic and acquired genomic changes accumulate over the human lifespan? Do childhood adversities result in biological changes that persist into adulthood? Can an adult who was exposed to childhood adversities be identified as "at risk" for developing disease based on their epigenetic, gene expression, telomeric, chromosomal instability, and/or cortisol level profiles? To answer these questions we will study 736 twins who have completed intense phenotypic behavioral evaluations in previous studies (completed 2 to 15 years ago) and represent two risks groups: (1) twins experiencing the extreme childhood adversity event of sexual abuse; and (2) twins experiencing a broad spectrum of social experiences. Cohort 1 (ages 40-55) will comprise a selected sample of 50 identical twin pairs who are discordant for a history of childhood sexual abuse, as well as 50 identical concordant pairs who did (25 pairs) or did not (25 pairs) experience sexual abuse as a child. The biological endpoints that will be measured and compared between co-twins for this cohort include: (1) frequencies and locations of genome-wide methylation changes using a sequence-based approach; (2) chromosome-specific telomere lengths; (3) frequencies of acquired chromosomal instability; (4) patterns of gene expression; and (4) diurnal basal salivary cortisol levels. Cohort 2 (ages 20-30) will be comprised of a normative sample of monozygotic (157 pairs) and dizygotic (111 pairs) twin pairs for whom behavioral phenotypes have been carefully determined throughout adolescence into young adulthood. The data gained from the study of these twins will provide insight as to the potential cumulative effect of multiple adversities on embedded biological changes. The biological endpoints to be measured for this cohort (for whom blood samples have been previously collected and are readily available) include: (1) frequencies and locations of genome-wide methylation changes using array based methodology; and (2) gene expression patterns. Collectively, comparisons of observed alterations in biological endpoint measures (within and between twins) to phenotypic data collected from multiple stages in the human lifespan will allow us to deduce the extent to which the observed differences in biomarkers are influenced by childhood adversity, adult adversity, and/or other environmental stressors. The data from this investigation will lead to the first direct estimate of the frequency of epigenetic, telomere length, acquired chromosomal instability, gene expression, and/or cortisol level changes that arise in adults due to childhood adversities. PUBLIC HEALTH RELEVANCE: The potential that environmental and social events can be biologically "remembered" to result in an individual having an increased risk for developing health conditions many years later has only recently been recognized. In this study we will identify potential mediators of this biological memory by recognizing changes in genomic and epigenomic patterns that are acquired in adults as a result of adverse (as well as positive) childhood events. By collecting this information from our unique population of twins, which includes a selected sample of discordant identical pairs, as well as a population sample of identical and fraternal twins, we can determine if observed behavioral and health outcomes are associated with specific genetic or epigenetic changes. The data collected from this study will establish a relationship between the long-term, cumulative biological effects of early-life stresses on disease. Moreover, the information gained from this study could be exploited to develop a biomarker assay to recognize individuals who are at "at risk" for acquiring illnesses, and/or lead to the development of therapeutic interventions to reduce adverse health outcomes.