Environmental, Genetic, and Epigenetic Mechanisms for Hormonal Change

项目摘要。了解青春期的遗传和环境调节因子已经成为一个话题， 越来越紧迫。认识到青春期过渡对整个生命周期的健康的重要性， NIH/NICHD发布PA-18-033，青春期生殖过渡的特征，以征求 申请填补青春期发展知识库中的重要空白的项目， 包括增加我们对“生活方式因素和环境暴露的影响”的理解。我们 研究旨在确定影响青春期的具体和潜在的可改变的环境因素， 我们认为遗传和表观遗传数据是实现这一目标的重要工具。我们的项目 将使用来自两个独立样本的数据，这两个样本都结合了联合收割机纵向激素和表观遗传数据， 丰富的环境风险措施。主要发现样本将是N = 1000个个体， 德州双胞胎计划的父母我们已经收集了关于这一群体的大量基线数据， 我们将利用这些现有数据建立一个跨越青春期的加速纵向研究，包括一个 深度表型分型子样本，最多8个评估波。复制数据集是现有资源 在青春期早期招募了N = 214名儿童，并在间隔2年后重新评估。这些独特的 数据集将使我们能够实现三个目标。首先，我们将应用统计遗传学的尖端方法 与之前关于生殖里程碑的强有力的全基因组关联研究（GWAS）的结果相比， 为了（a）开发和验证更强大的多基因评分，这是一个基因组范围内的措施， 个体对早期生殖发育的遗传倾向;以及（B）探讨遗传倾向对早期生殖发育的影响程度。 责任直接通过个人自身的生物学运作，而不是通过环境提供的 父母（“遗传养育”）。其次，我们将使用纵向，双胞胎对照数据的DNA甲基化（DNAm） 跨越青春期过渡，建立一个新的“青春期年龄”表观遗传时钟，并将验证这个时钟， 一个独立的复制样本。开发环境响应的分子生物标志物 青春期发育的加速有可能彻底改变青春期研究，就像现有的一样。 表观遗传时钟彻底改变了衰老研究。第三，我们将测试如何建立环境风险 早期和加速青春期发育的因素（包括早期生活压力，集中的社区 贫困和生父缺失）与遗传影响相互作用，使用三项研究设计， 不同的优势和局限性-双胞胎，测量基因和表观遗传设计。总体而言，拟议 研究有可能产生非常高的影响，通过提供科学界的经验， 关于青春期遗传和环境调节因子相互作用的见解， 方法学工具（多基因评分和表观遗传时钟算法），可广泛应用于研究 青春期发育个体差异的生物学和环境机制及其后遗症。

Project Summary. Understanding the genetic and environmental regulators of puberty has become a topic of increasing urgency. Recognizing the importance of the pubertal transition for health across the lifespan, NIH/NICHD issued PA-18-033, Characterization of the Adolescent Reproductive Transition to solicit applications for projects that will fill essential gaps in the knowledge base regarding pubertal development, including increasing our understanding of the “influences of lifestyle factors and environmental exposures.” Our research aims to identify specific and potentially modifiable environmental factors that influence pubertal development; we view genetic and epigenetic data as essential tools for accomplishing that goal. Our project will use data from two independent samples that both combine longitudinal hormonal and epigenetic data with rich measures of environmental risk. The primary discovery sample will be N = 1000 individuals and their parents from the Texas Twin Project. We have already collected considerable baseline data on this cohort, and we will leverage this existing data to build an accelerated longitudinal study spanning adolescence, including a deep phenotyped sub-sample with up to 8 assessment waves. The replication data set is an existing resource of N = 214 children recruited in early puberty and re-assessed after a 2-year interval. Together, these unique datasets will allow us to accomplish three aims. First, we will apply cutting-edge methods in statistical genetics to findings from previous, well-powered genome-wide association studies (GWAS) of reproductive milestones in order to (a) develop and validate more powerful polygenic scores that are genome-wide measures of an individual’s genetic liability toward earlier reproductive development; and (b) probe the extent to which genetic liabilities operate directly through the individual’s own biology versus through the environment provided by parents (“genetic nurture”). Second, we will use longitudinal, co-twin-control data on DNA methylation (DNAm) across the pubertal transition to build a novel epigenetic clock for “pubertal age” and will validate this clock in an independent replication sample. Developing a molecular biomarker for environmentally-responsive accelerations in pubertal development has the potential to revolutionize puberty research, just as existing epigenetic clocks have revolutionized aging research. Third, we will test how established environmental risk factors for early and accelerated pubertal development (including early life stress, concentrated neighborhood poverty, and biological father absence) interact with genetic influences using a trio of research designs with different strengths and limitations – twin, measured gene, and epigenetic designs. Overall, the proposed research has potential to have very high impact, by providing the scientific community both with empirical insights regarding the interplay of genetic and environmental regulators of puberty and with openly-available methodological tools (polygenic scoring and epigenetic clock algorithms) that can be broadly applied to study biological and environmental mechanisms of individual variation in pubertal development and its sequelae.