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

糖尿病相关的疾病易感性是发病、死亡和减少的最常见原因。 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- 相关疾病以前没有定义或与遗传变异有关。我们最近 提出了一种新的范式，用于理解DNA序列变异之间的关系， 表观遗传标记和表型，认为基因和表观遗传学的作用，不仅影响 一个表型的平均值，还有它的可塑性，或者说变异。我们已经开始应用我们的方法， 鉴定人类基因组中高度甲基化的区域（VMR）。我们发现 VMR定义了老年个体的表观遗传特征，并且它们与重要的 健康指数，如BMI。本提案的目的是充分探讨这一新模式， 鉴定与跨越3个域（身体）的常见年龄相关表型相关的VMR 组成;能量可用性/需求;维持身体稳态），并确定 VMR与潜在遗传变异之间的关系。除了传统的观点， 基因型直接控制预期（或平均）表型值，我们认为，另一个主要的影响， 基因型是控制随机表观遗传变异，导致甲基化的变异性增加， 特定的基因组位点和随之增加的表型变异。这是一个全新的 概念.我们假设一种新的SNP，我们称之为vSNP，或变异SNP， VMR的甲基化变异程度，而不是平均甲基化水平，因此也 与群体中表型的扩散或变异性相关，而不是与平均值相关。 这样的vSNP将增加处于疾病的高风险和低风险的个体的比例，因此， 在传统的关联分析中是无法检测到的。为了支持我们的方法，我们展示了 鉴定与VMR相关的vSNP，与增加的表型变异相关的vSNP， 与表型相关的VMR。我们的目标是：1 -研究DNA之间的关系 序列，DNA甲基化和定量老化表型，根据我们的平均值和 可塑性模型，使用2000名参与者在巴尔的摩纵向研究老化（BLSA）， 以及全基因组SNP和甲基化方法。2 -进行聚焦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 负责目标1中的发现。这项工作将有助于阐明遗传变异如何与 甲基化变异以及两者如何影响增加疾病的年龄相关表型 易感性DNA甲基化可能是风险评估和干预的新目标， 减少疾病和残疾的负担，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.