Environmental, Genetic, and Epigenetic Mechanisms for Hormonal Change

荷尔蒙变化的环境、遗传和表观遗传机制

• 批准号: 9980434
• 负责人: Kathryn Paige Harden
• 金额: $ 58.44万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980434
• 关键词: Acceleration; Address; Adolescence; Adolescent; Adrenal hormone preparation; Adult; Age; Age at Menarche; Aging; Algorithms; Alleles; Biological; Biology; Child; Communities; DNA; DNA Methylation; Data; Data Set; Development; Economics; Environment; Environmental Exposure; Environmental Monitoring; Environmental Risk Factor; Epigenetic Process; Family; Fathers; First Births; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Goals; Gonadal Hormones; Health; Health Transition; Health behavior; Height; Hormonal; Hormonal Change; Individual; Individual Differences; Investigation; Life Style; Longevity; Longitudinal Studies; Measures; Mental Health; Methodology; Methods; Methylation; Modification; National Institute of Child Health and Human Development; Neighborhoods; Onset of illness; Parents; Participant; Patient Self-Report; Phenotype; Population Study; Poverty; Psyche structure; Puberty; Reproductive Behavior; Research; Research Design; Research Personnel; Resources; Rest; Risk; Risk Factors; Sampling; Shapes; Sleep; Smoking; Statistical Methods; Stress; Testing; Texas; Twin Multiple Birth; United States National Institutes of Health; cohort; critical period; design; early life stress; epigenome; food insecurity; genetic information; genetic variant; genome wide association study; genome-wide; indexing; individual variation; insight; knowledge base; lifestyle factors; longitudinal design; molecular marker; novel; offspring; physical conditioning; programs; puberty transition; recruit; reproductive; reproductive development; reproductive function; social; socioeconomic disadvantage; socioeconomics; tool; trait; virtual; walkability

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.

项目摘要。了解青春期的遗传和环境调节因子已成为一个话题 紧迫性。认识到青春期过渡在整个生命周期中的重要性， NIH/NICHD发行了PA-18-033，青少年生殖过渡的表征 申请将填补有关青春期发展知识基础基本空白的项目的申请， 包括我们对“生活方式因素和环境暴露的影响”的理解。我们的 研究旨在确定影响青春期的特定和潜在可修改的环境因素 发展;我们将遗传和表观遗传数据视为完成该目标的重要工具。我们的项目 将使用来自两个独立样本的数据，这些数据都将纵向激素和表观遗传数据与 丰富的环境风险衡量。主要发现样本将为n = 1000个人及其 来自德克萨斯双胞胎项目的父母。我们已经收集了有关此队列的大量基线数据，并且 我们将利用这些现有数据来构建跨越青少年的加速纵向研究，包括 深层表型子样本，最多8个评估波。复制数据集是现有资源 n = 214名儿童在青春期早期招募，并在2年间隔后重新评估。在一起，这些独特 数据集将使我们能够实现三个目标。首先，我们将在统计遗传学中应用尖端方法 从生殖里程碑的先前，全基因组的关联研究（GWAS）的发现 为了（a）发展和验证更强大的多基因分数，这是全基因组的测量 个人对早期生殖发展的遗传责任； （b）探测遗传的程度 负债直接通过个人自己的生物学而实施，而不是通过由 父母（“遗传护士”）。其次，我们将在DNA甲基化（DNAM）上使用纵向，共同控制数据 在整个青春期过渡中，为“青春期”建立一个新颖的表观遗传时钟，并将在 独立复制样本。开发用于环境响应的分子生物标志物 青春期开发的加速有可能彻底改变青春期研究 表观遗传钟已经彻底改变了衰老研究。第三，我们将测试确定的环境风险 早期和加速的青春期发展的因素（包括早期生活压力，集中邻居 贫困和生物学父亲的缺席）与三个研究设计与遗传影响相互作用 不同的优势和局限性 - 双，测量基因和表观遗传学设计。总体而言，提议 通过为科学界提供经验，研究有可能产生很大的影响 有关青春期遗传和环境调节剂相互作用以及公开可用的见解 可以广泛应用的方法学工具（多基因评分和表观遗传时钟算法） 青春期发育及其后遗症中个体变异的生物学和环境机制。