Molecular signatures of health and life span disparities between whites and African-Americans in the APOE region

描述（由申请人提供）：延长健康寿命是发达国家社会面临的一个新问题。生物学和遗传学专家认为，通过揭示基因变异，可以实现该领域的重大突破，这些变异可能涉及晚年健康、幸福和生存特征的表型调节。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，而直接进化选择强化了生命过程中塑造基因对几代人的健康、福祉和生存的影响。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。本提案的目的是通过揭示遗传因素与生理和行为内表型（EPs）的关联，通过确定其在发病率（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风险中的作用，确定遗传因素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。通过阐明与生命历程相关的过程在形成风险结果的遗传影响中的作用，并通过将遗传因素的影响与世代内和跨代男性和女性的生命历程相结合。为了实现这一目标，我们将使用弗雷明汉心脏研究、健康与退休研究（与医疗保险数据相关）、年轻人冠状动脉风险发展研究和长寿家庭研究中不同世代个体的丰富数据。以下具体目标将被处理。目的1。表型的构建。目标2。EPs的遗传关联鉴定。目标3。鉴定与发病、残疾和死亡风险的遗传关联。目标4。阐明揭示的遗传变异在健康、幸福和生存中的系统作用，并进行动态整合。目标5。剖析基因在揭示的snp中的生物学作用。

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.