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、丹麦和美国现有的7个纵向双胞胎和家庭研究中进行新的合作，通过协调这些数据集，为未来基因-环境相互作用的研究奠定基础。中心焦点是可能与中年和老年结果相关的社会数据。这些研究采用了与3个结果领域相关的各种测量方法：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一些社会环境指标（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，他们的基线年龄在24岁到90岁之间，并进行了长达26年的纵向随访。我们建议利用这些研究尚未开发的潜力来考虑社会背景和晚年结果之间相互作用的问题。第一步将是使用DataSHaPer等工具来协调测量结果和暴露（1年级）的变量，以识别重叠的项目内容和回答格式，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元分析和综合数据分析。利用现有数据，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差异以及测量的基因和环境。在确定这种关系存在之后，我们将在瑞典、丹麦和美国样本中纳入炎症标记物和/或基因（例如CRP和IL-6）的测量，作为第一个具体步骤，以展示这些遗传信息丰富的双胞胎材料（第3和4年）之间合作的附加价值。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记和/或基因型（Yrs 4&5）。使用统一的数据，纵向和横断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)部分通过选择过程维持，即高功能个体创造加强其高功能的环境（GE相关性）；功能变化：a)主要反映环境因素的影响，b)如双胞对照方法所示，环境因素部分由身体、智力和社会活动的个体差异介导；基因对一个区域功能的影响可以被其他区域的因素所缓和。这种适度可以压倒基因的影响（当身体残疾通过破坏个人控制环境的能力来影响情感或认知功能时）。或者，适度可以通过触发遗传脆弱性的因素来实现，否则这些因素可能不会被表达出来（如当心理社会压力触发对身体疾病的遗传脆弱性的表达时）。

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.