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

描述(申请人提供)：在这项申请中，我们建议瑞典、丹麦和美国现有的7项纵向双胞胎和家庭研究之间的新合作，以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。中心焦点是社交数据，这些数据可能与中年和老年的结果有关。这些研究有与3个结果领域相关的各种衡量标准：身体功能和健康、心理健康(情绪稳定/抑郁)和认知健康。这些研究分享了从儿童早期到成年的许多社会环境指标(例如，社会背景、早期生活经历、社会经济状况)。总而言之，我们有7105对双胞胎的数据，年龄从24岁到90岁，以及长达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关于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等工具协调衡量结果和暴露(1年)的变量，以确定重叠的项目内容和回答格式，应用最先进的心理测量学分析，通过IRT因素方法建立测量差异，并根据需要对汇集数据进行荟萃分析和综合数据分析。利用现有的数据，我们将利用孪生设计的优势来评估GxE和GE的相关性，同时考虑到遗传和环境差异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、丹麦和美国的样本中纳入炎症标志物和/或基因(例如，CRP和IL-6)的测量，作为展示这些具有遗传信息的孪生材料(年3和年4)合作的附加值的第一个具体步骤。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/或基因类型(年限4&5年)。使用协调一致的数据，纵向和横断面分析将通过检验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)部分通过选择过程保持，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调节，如共同双胞胎控制方法所示；基因对一个区域的功能的影响可以被其他区域的因素所缓和。这种适度可以压倒遗传影响(当身体残疾通过扰乱个人控制环境的能力来影响情绪或认知功能时)。或者，适度可以是触发遗传脆弱性的因素，否则这些脆弱性可能不会表现出来(例如，当心理社会压力触发对身体疾病的遗传脆弱性的表现时)。 公共卫生相关性：以前的研究已经牢固地确立了社会因素与晚年健康和功能之间的联系。然而，这项研究没有解释这些联系的基础，也没有解释社会影响如何与已知的有助于晚年功能的生物和遗传因素相互关联。我们将建立一个由七项纵向双胞胎研究组成的联盟，以探索社会因素与老龄化结果之间的联系的基础。结果分析了16,000多名参与者的综合数据，目的是理解为什么早期生活逆境、孤立和孤独等社会因素与包括死亡率、身体、情感和认知健康在内的不同结果有关。

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.