Gene-Environment Interplay of Social Contexts and Aging-Related Outcomes

描述（由申请人提供）：在本申请中，我们提议在瑞典、丹麦和美国的7项现有纵向双胞胎和家族研究之间进行新的合作，通过协调这些数据集为未来的基因-环境相互作用研究奠定基础。中心焦点是可能与中年和老年结果有关的社会数据。这些研究有各种与3个结果领域相关的指标：身体功能和健康，心理健康（情绪稳定/抑郁）和认知健康。这些研究分享了从幼儿期到成年期的社会环境的一些指标（例如社会背景、早期生活经历、社会经济地位）。总的来说，我们有7105对双胞胎的数据，基线时年龄为24岁至>90岁，纵向随访长达26年。我们建议利用这些研究尚未开发的潜力，考虑社会背景和晚年结果之间的相互作用的问题。第一步将是使用DataSHaPer等工具协调测量结果和暴露（第1年）的变量，以确定重叠的项目内容和响应格式，应用最先进的心理测量分析，通过IRT因子方法建立测量方差，并根据需要对汇总数据进行Meta分析和综合数据分析。利用现有的数据，我们将利用双胞胎设计的优势来评估GXE和GE相关性，同时考虑遗传和环境方差以及测量的基因和环境。在确定存在这种关系后，我们将在瑞典，丹麦和美国样本中纳入炎症标志物和/或基因（例如CRP和IL-6）的测量，作为第一个具体步骤，以证明这些遗传信息双胞胎材料之间的合作附加值（第3和4年）。最后，我们将在GXE和GE相关性的相关分析中探索其他生物标志物和/或基因型（第4和5年）。使用协调的数据，纵向和横截面分析将通过测试以下假设来评估晚年功能中基因-环境相互作用的概念模型：功能的稳定特征：a）主要反映遗传因素的持久影响，但B）部分通过选择过程得以维持，高功能个体通过选择过程创造加强其高功能的环境。（GE相关性）;功能的变化：a）主要反映环境因素的影响，B）部分由身体，智力和社会活动的个体差异介导，如双胞胎对照方法所示;遗传对一个领域功能的影响可以由其他领域的因素调节。这种适度可以压倒遗传的影响（如身体残疾通过破坏个人控制环境的能力而影响情感或认知功能）。或者，适度可以是触发基因脆弱性的因素，这些因素可能不会被表达出来（如当心理社会压力触发基因对身体疾病的脆弱性表达时）。 公共卫生相关性：以前的研究已经牢固地建立了社会因素与晚年健康和功能的关联。然而，这项研究并没有解释这些关联的基础，也没有解释社会效应如何与已知有助于晚年功能的生物和遗传因素相互关联。我们将建立一个由7个纵向双胞胎研究组成的联盟，以探索社会因素与老龄化结局之间关联的基础。对来自16，000多名参与者的综合数据进行分析，旨在了解为什么早期生活逆境，孤立和孤独等社会因素与死亡率，身体，情感和认知健康等多种结果相关。

DESCRIPTION (provided by applicant): In this application, we propose a new collaboration among 7 existing longitudinal twin and family studies in Sweden, Denmark, and the US to lay the foundation for future studies of gene-environment interplay through harmonization of these data sets. The central focus is social data that can be related to outcomes in midlife and old age. The studies have a variety of measures relevant to 3 outcome domains: physical functioning and health, psychological well-being (emotional stability/depression), and cognitive health. The studies share a number of indicators of social environment from early childhood through adulthood (e.g. social context, early life experiences, SES). In all, we have data from 7105 twin pairs, age 24 to >90 at baseline, and up to 26 years of longitudinal follow-up. We propose to exploit the as yet unharnessed potential of these studies for considering questions about interplay between social context and late-life outcomes. The first steps will be to harmonize variables that measure outcomes and exposures (Yr 1) using tools such as DataSHaPer to identify overlapping item content and response formats, apply state-of- the-art psychometric analysis to establish measurement variance via IRT-factor approaches, and conduct meta analyses and integrated data analysis of pooled data as warranted. Using existing data, we will capitalize on advantages of the twin design for evaluating GXE and GE correlation, considering both genetic and environmental variance and measured genes and environments. After establishing that such relations exist, we will incorporate measures of inflammatory markers and/or genes (e.g. CRP and IL-6) in Swedish, Danish and American samples as a first concrete step to demonstrate added value of collaboration across these genetically informative twin materials (Yrs 3&4). Finally, we will explore other biological markers and/or genotypes) in relevant analyses of GXE and GE correlation (Yrs 4&5). Using harmonized data, longitudinal and cross-sectional analyses will evaluate conceptual models of gene- environment interplay in late-life functioning by testing the following hypotheses: That stable features of functioning: a) primarily reflect enduring influences of genetic factors, but b) are maintained in part through selection processes whereby high-functioning individuals create environments that reinforce their high functioning (GE correlation); that changes in functioning: a) primarily reflect the influences of environmental factors which b) are mediated in part by individual differences in physical, intellectual, and social activity, as shown by co-twin control methods; and that genetic influences on function in one area can be moderated by factors in other areas. This moderation can overwhelm genetic influences (as when physical disability impacts emotional or cognitive functioning by disrupting individuals' ability to control their environments). Alternatively, moderation can be by factors that trigger genetic vulnerabilities that might not otherwise be expressed (as when psychosocial stress triggers expression of genetic vulnerabilities to physical illness). PUBLIC HEALTH RELEVANCE: Previous research has firmly established the association of social factors with late-life health and functioning. Yet this research does not explain the basis for these associations or how social effects interrelate with the biological and genetic factors known to contribute to late-life functioning. We will establish a consortium of seven longitudinal twin studies to explore the basis for the association of social factors and aging outcomes. The resulting analysis of the combined data from over 16,000 participants aims to understand why early life adversity, social factors such as isolation and loneliness are associated with diverse outcomes including mortality, and physical, emotional and cognitive health.