GENES AND OTHER FACTORS AFFECTING AGING CHANGES: EFFECTS ON HEALTH AND LIFESPAN

计划2 项目2的目标是显著提高我们对复杂遗传学的理解， 调节人类衰老，并调查影响生理的遗传因素的相关性 身体的衰老变化与重大疾病的风险和长寿有关。为了实现这一目标，我们将 识别单独和共同影响生理老化标记的遗传变异 在这个项目中指定的，使用通过dbGaP提供的纵向人类数据集。一个特殊 研究的重点将是多效性效应（拮抗和非拮抗）的一个 基因型对不同性状的影响，以及一个性状在不同年龄的影响。具体目标：1）评估个人和 SNPs对生理衰老标记的加性多基因影响。为此，我们将进行一次 本项目中规定老化表型的无假设GWAS，并评估个体和关节 使用多基因风险评分，选择的遗传变异对衰老表型的（加性）影响; 2） 研究单个SNP的多效性（拮抗性和非拮抗性）效应， 在目标1中评估的关于本项目中指定的衰老特征以及关于健康和 在另外两个项目中评估的长寿性状。我们将测试关于多效性的假设（包括 权衡）基因型对以下的影响：（i）不同的性状;和（ii）不同年龄的一个性状。3)探讨 与Aim 1中检测到的SNP相关的基因/调控元件之间的功能关系。为此， 我们将使用在线资源和工具进行SNPs/基因/蛋白质注释，基因功能， 途径分析，以确定与检测到的基因最相关的生物学功能，并研究 他们参与已知的衰老途径和网络。4)评价上位性遗传影响 生理老化的标志我们将选择SNPs的子集，因为它们：a）对衰老的多效性作用 目标2中检测到的表型; B）与目标3中涉及相似生物学功能的基因相关; c） 参与衰老相关的途径。对于这些SNP子集，我们将评估上位性遗传学， 这项研究的结果将大大提高我们对衰老表型的理解， 衰老的遗传调节，以及它在健康和长寿中的作用。

Project 2 The objective of the Project 2 is to significantly improve our understanding of complex genetic regulation of human aging, and investigate relevance of genetic factors influencing physiological aging changes in body to risks of major diseases and to longevity. To address this objective, we will identify genetic variants which individually and jointly influence markers of physiologicalaging specified in this project, using sets of longitudinal human data available through dbGaP. A special emphasis of the research will be on pleiotropic effects (both antagonistic and non-antagonistic) of a genotype on different traits, and on one trait at different ages. Specific Aims: 1) Evaluate individual and additive polygenic influence of SNPs on markers of physiological aging. For this we will conduct a hypothesis-free GWAS of aging phenotypes specified in this project and evaluate individual and joint (additive) effects of selected genetic variants on the aging phenotypes, using polygenic risk scores; 2) Investigate pleiotropic (both antagonistic and non-antagonistic) effects of individual SNPs and polygenic scores evaluated in Aim 1 on aging traits specified in this project, and on health and longevity traits evaluated in two other projects. We will test hypotheses about the pleiotropic (including trade-offs)influence of a genotype on: (i) different traits; and (ii) one trait at different ages. 3) Investigate functional relationships among genes/regulatory elements linked to SNPs detected in Aim1. For this, we will use online resources and tools for SNPs/genes/proteins annotating, gene-to-function and pathway analysis, to specify biological functions most relevant to the detected genes, and investigate their involvement in known aging pathways and networks. 4) Evaluate epistatic genetic influence on markers of physiological aging. We will select subsets of SNPs for their: a) pleiotropic effects on aging phenotypes detected in Aim 2; b) relation to genes involved in similar biological functions in Aim 3; c) involvement in aging-related pathways. For these subsets of SNPs, we will evaluate epistatic genetic effects on aging phenotypes.Results of this study will significantly improve our understanding of genetic regulation of aging, and its role in health and longevity.