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

描述（由申请人提供）：发达国家社会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遗传变异来实现，这些变异可以参与调节晚年健康，幸福和生存的表型。一个令人困惑的问题是，晚年的表型并不是直接进化选择的结果，进化选择加强了生命过程对健康、福祉和生存的遗传影响的作用。分析生命过程在遗传效应中的作用并不是全基因组关联研究的主流标准策略。该提案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，通过确定其在发病风险中的作用，确定遗传和非遗传因素对生命过程中健康、福祉和生存的系统性贡献（心血管疾病（CVD）和癌症）、残疾、死亡率和CVD和癌症导致的死亡率，通过阐明与生命过程有关的过程在形成对风险结果的遗传影响方面的作用，并通过将遗传因素的影响与男女的生命过程结合起来，在一代人和跨代人之间进行。为了实现这一目标，我们将使用来自不同世代的个人的丰富数据，这些数据来自心脏病研究、与医疗保险数据相关的健康和退休研究、年轻人冠状动脉风险发展研究和长寿家庭研究。将讨论以下具体目标。目标1.表型的构建。目标2.识别与EP的遗传关联。目标3.识别与发病率、残疾和死亡风险的遗传关联。目标4。阐明所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。目标5。剖析揭示的SNP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.