Life Course and Genetic and Non-genetic Factors in Health and Survival

描述(申请人提供)：发达国家社会面临的一个新问题是延长健康寿命。生物学和遗传学专家认为，该领域的重大突破可以通过揭示基因变异来实现，这些变异可以参与调节表征健康、幸福和晚年生存的表型。一个令人费解的问题是，晚年的表型并不是直接进化选择的结果，直接进化选择强化了生命过程的作用，塑造了几代人内部和跨代人对健康、福祉和生存的遗传影响。分析生命过程在遗传效应中的作用S没有在全基因组关联研究的主流策略中发挥作用。这项建议的目的是通过揭示遗传因素与生理和行为内表型(EP)的关联，通过确定它们在发病率(心血管疾病和癌症)、残疾、死亡和可归因于心血管疾病和癌症的死亡中的作用，通过阐明与生命过程相关的过程在形成对风险结果的遗传影响中的作用，以及通过将遗传因素的影响与世代内和跨代人的谎言过程相结合，来确定遗传因素和非遗传因素对生命过程中的健康、福祉和生存的系统性贡献。为了实现这一目标，我们将在Framingham心脏研究、与Medicare数据相关联的健康和退休研究、青年冠状动脉风险发展研究和长寿家庭研究中使用不同世代个人的丰富数据。将实现以下具体目标。目的1.表型的构建。目的2.确定EPs的遗传关联。目的3.确定与发病、残疾和死亡风险有关的遗传因素。目的4.阐明已揭示的遗传变异在健康、福祉和生存中的系统作用，并进行动态整合。目的5.剖析已发现的SNPs基因的生物学作用。

DESCRIPTION (provided by applicant): An emerging problem for societies in developed countries is extending years of healthy life. Specialists in biology and genetics argue that major breakthrough in the field can be achieved by revealing genetic variants which can be involved in regulation of phenotypes characterizing health, wellbeing and survival in late life. A puzzling problem is that phenotypes in late life are not the result of direct evolutionary selection that reinforces the role of the life course processes shaping genetic effects on health, wellbeing and survival within and across generations. Analysis of the role of the life course in genetic effects s not in mainstream of standard strategies of genome-wide association studies. The objective of this proposal is to identify systemic contribution of genetic and non-genetic factors to health, wellbeing, and survival over the life course by revealing associations of genetic factors with physiological and behavioral endophenotypes (EPs), by identifying their roles in risks of morbidity (cardiovascular disease (CVD) and cancer), disability, mortality, and mortality attributed to CVD and cancer, by elucidating the role of life-course related processes in shaping genetic effects on the risk outcomes, and by integrating the effects of genetic factors with the lie course in men and women within and across generations. To achieve this goal, we will use rich data on individuals from different generations longitudinally followed in the Framingham Heart Study, Health and Retirement Study linked with Medicare data, the Coronary Artery Risk Development in Young Adults study, and the Long Life Family Study. The following Specific Aims will be addressed. Aim 1. Construction of phenotypes. Aim 2. Identification of genetic associations with EPs. Aim 3. Identification of genetic associations with risks of morbidity, disability, and mortality. Aim 4. Elucidating systemic role of the revealed genetic variants in health, wellbeing, and survival and conducting dynamic integration. Aim 5. Dissecting biological role of genes for the revealed SNPs.