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已经成为一个主题 迫切性越来越强。认识到青春期过渡对终生健康的重要性， NIH/NICHD发布PA-18-033，青少年生殖过渡的特征征集 申请将填补青春期发育知识库中基本空白的项目， 包括增加我们对“生活方式因素和环境暴露的影响”的理解。我们的 研究的目的是确定影响青春期的特定的和潜在的可改变的环境因素 发展；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，这两个样本都将纵向激素和表观遗传学数据与 丰富的环境风险衡量标准。主要的发现样本将是N=1000个人及其 德克萨斯双胞胎项目的父母。我们已经收集了关于这一队列的大量基线数据，并且 我们将利用这些现有数据来建立一个跨越青春期的加速纵向研究，包括 深表型亚样，最多有8个评估波。复制数据集是现有资源 N=214名在青春期早期招募的儿童，并在两年后重新评估。总而言之，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中的尖端方法 与之前对生殖里程碑进行的强大的全基因组关联研究(GWAS)的发现相一致 为了(A)开发和验证更强大的多基因得分，这些得分是基因组范围内的 个体对较早生殖发育的遗传易感性；及(B)探讨遗传因素在多大程度上 负债直接通过个人自身的生理作用，而不是通过 父母(“基因养育”)。其次，我们将使用关于DNA甲基化(DNaM)的纵向、共同对照数据 通过青春期过渡来建立一个新的表观遗传学时钟来应对青春期年龄，并将在 一个独立的复制样本。环境友好型分子生物标记物的研制 青春期发育的加速有可能像现有的那样，给青春期研究带来革命性的变化。 表观遗传时钟使衰老研究发生了革命性的变化。第三，我们将测试已建立的环境风险 青春期发育早期和加速的因素(包括早期生活压力、集中的邻里 贫困和生父缺失)与基因影响相互作用，使用了三个研究设计 不同的优势和局限性-双胞胎、可测量的基因和表观遗传设计。整体而言，建议的 研究有可能产生非常高的影响，因为它为科学界提供了经验 关于青春期遗传和环境调节因素相互作用的见解 可广泛应用于研究的方法学工具(多基因评分和表观遗传时钟算法) 青春期发育及其后遗症个体差异的生物学和环境机制。

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.