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

描述（由申请人提供）：影响人类健康的几种最常见疾病（心血管疾病;糖尿病;癌症）的病因学涉及心理社会影响。据推测，这些心理社会影响是通过基于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很少，许多问题仍然存在：表观遗传和获得性基因组变化在人类寿命中积累到什么程度？童年的逆境是否会导致持续到成年的生物变化？一个成年人谁是暴露于童年逆境被确定为“风险”发展疾病的基础上，他们的表观遗传，基因表达，端粒，染色体不稳定性，和/或皮质醇水平的配置文件？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（2至15年前完成）中完成了严格的表型行为评估，并代表两个风险群体：（1）经历过性虐待极端童年逆境事件的双胞胎;和（2）经历广泛社会经历的双胞胎。队列1（年龄40-55岁）将包括50对同卵双胞胎的选定样本，这些双胞胎在儿童期性虐待史上不一致，以及50对相同的一致对，他们在儿童期曾（25对）或未（25对）经历过性虐待。将在该队列的双胞胎之间测量和比较的生物学终点包括：（1）使用基于序列的方法的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;和（4）昼夜基础唾液皮质醇水平。队列2（年龄20-30岁）将由同卵（157对）和异卵（111对）双胞胎对的标准样本组成，在整个青春期至青年期期间仔细确定了其行为表型。从这些双胞胎的研究中获得的数据将提供关于多种逆境对嵌入式生物变化的潜在累积效应的见解。对于该群组（其血液样品先前已经收集并且容易获得）要测量的生物学终点包括：（1）使用基于阵列的方法的全基因组甲基化变化的频率和位置;和（2）基因表达模式。总的来说，将观察到的生物学终点指标（双胞胎内和双胞胎之间）的变化与从人类寿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儿童逆境，成人逆境和/或其他环境压力因素影响的程度。这项调查的数据将导致第一次直接估计的频率表观遗传，端粒长度，获得性染色体不稳定性，基因表达，和/或皮质醇水平的变化，出现在成年人由于童年的逆境。 公共卫生相关性：环境和社会事件可能被生物学“记忆”，导致个人在多年后患健康状况的风险增加，这一点直到最近才被认识到。在这项研究中，我们将通过识别成人因不良（以及积极）童年事件而获得的基因组和表观基因组模式的变化来确定这种生物记忆的潜在介质。通过从我们独特的双胞胎群体中收集这些信息，其中包括选定的不一致的同卵双胞胎样本，以及同卵和异卵双胞胎的群体样本，我们可以确定观察到的行为和健康结果是否与特定的遗传或表观遗传变化相关。从这项研究中收集的数据将建立早期生活压力对疾病的长期累积生物效应之间的关系。此外，从这项研究中获得的信息可以用来开发一种生物标志物测定法，以识别处于患病“风险”的个体，和/或导致开发治疗干预措施，以减少不良健康结果。

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.