The Role and Genetic Mechanism of Epigenetic Plasticity in Age-Related Disease

与年龄相关的疾病易感性是导致发病率、死亡率和死亡率下降的最常见原因。 生活质量。虽然可能与遗传学和表观遗传学有关，但表观遗传学对年龄的影响- 相关疾病以前没有被定义，也没有与遗传变异有关。我们最近做了 提出了一种理解DNA序列变异之间关系的新范式， 表观遗传标记和表型即考虑基因和表观遗传的作用，不仅影响 一个表型的平均值，也是它的可塑性或变异度。我们已经开始应用我们的方法，通过 识别人类基因组中高度可变的甲基化区域(VMR)。我们发现， VMR定义了老年人的表观遗传学特征，并认为它们与重要的 身体质量指数等健康指标。这项提议的目的是通过以下方式充分探索这一新范式 确定与3个领域(身体)的常见年龄相关表型相关的VMRS 组成；能量供应/需求；维持身体动态平衡)，并确定 VMRS与潜在的遗传变异的关系。除了传统的观点外， 基因类型直接控制预期(或平均)表型值，我们认为另一个主要影响 基因分型是为了控制随机的表观遗传变异，导致甲基化的变异性增加。 特定的基因组位置和随之而来的表型变异增加。这是一个戏剧性的新 概念。我们假设了一种新的SNP，我们称之为vSNP，或变异SNP，它与 与VMRS的甲基化变异性程度，而不是平均甲基化水平，因此也 与群体中表型的分布或变异性有关，而不是平均值。 这样的vSNP将增加疾病高风险和低风险个体的比例，从而 在传统的关联分析中是检测不到的。为了支持我们的方法，我们展示了 识别与VMRS相关的vSNP、与增加的表型差异相关的vSNP的初步数据， VMRS与表型相关。我们的目标是：1-研究DNA与 序列、DNA甲基化和定量衰老表型在我们的平均值和 塑性模型，使用了巴尔的摩老龄化纵向研究(BLSA)的2000名参与者， 以及全基因组的SNP和甲基化方法。2-执行聚焦DNA测序 并捕获亚硫酸氢盐测序以鉴定特定序列和表观遗传变体 负责AIM 1中的发现。这项工作将有助于阐明基因变异与 甲基化变异及其对增加疾病的年龄相关表型的影响 敏感度。DNA甲基化可能成为风险评估和干预的新目标， 减轻疾病和残疾的负担，减缓衰老的有害影响。

Age-related susceptibility to disease is the most common cause of morbidity, mortality, and diminished quality of life. Although likely related to both genetics and epigenetics, the epigenetic influences on age- related disease have not been defined previously or related to genetic variation. We have recently proposed a novel paradigm for understanding the relationship between variation in DNA sequence, epigenetic marks, and phenotype that considers the role of genes and epigenetics in affecting not only the mean of a phenotype but also its plasticity, or variance. We have begun to apply our approach by identifying highly variably methylated regions (VMRs) in the human genome. We have discovered that VMRs define an epigenetic signature in aged individuals, and that they are associated with important health indicators such as BMI. The purpose of this proposal is to fully explore this new paradigm by identifying VMRs associated with common age-related phenotypes across 3 domains (body composition; energy availability/demand; maintenance of body homeostasis) and determine the relationship between VMRs and underlying genetic variation. In addition to the traditional view that genotypes directly control expected (or mean) phenotype values, we argue that another major effect of genotype is to control stochastic epigenetic variation leading to increased variability of methylation at a particular genomic site and to a consequent increased phenotypic variation. This is a dramatically new concept. We postulate a new kind of SNP, which we call a vSNP, or variation-SNP, that is associated with the degree of methylation variability at VMRs, rather than mean methylation level, and thus also associates with the spread, or variability, of a phenotype in a population rather than the mean value. Such a vSNP would increase the proportion of individuals at both high and low risk of disease, and thus would not be detectible in traditional association analyses. To support our approach, we show preliminary data identifying vSNPs related to VMRs, vSNPs related to increased phenotypic variance, and VMRs related to phenotype. Our aims are: 1 - To investigate the relationship between DNA sequence, DNA methylation, and quantitative aging phenotypes under both our mean and plasticity models, using 2000 participants in the Baltimore Longitudinal Study of Aging (BLSA), and genome-wide SNP and methylation approaches. 2 - To perform focused DNA sequencing and capture bisulfite sequencing to identify the specific sequence and epigenetic variants responsible for findings in Aim 1. This work will help elucidate how genetic variation relates to methylation variation and how both impact age-associated phenotypes that increase disease susceptibility. DNA methylation could be a new target for risk assessment and intervention that can reduce the burden of disease and disability and slow down the deleterious effects of aging.