What Genes Experience:Environmental Moderators of Genetic Risk in MIDUS

描述（由申请人提供）：拟议研究的中心目标是在美国成年人的大型国家研究中启动分子遗传学的新时代，称为MIDUS（美国中年人）。从1995年开始，MIDUS已成为从成年早期到晚年的多学科老龄化研究的主要论坛，拥有来自科学界的大量追随者（最常下载的数据集在国家老龄化计算机化数据档案馆）。这项研究的科学成果是广泛的（约400篇出版物），其中的关键主题阐明了MIDUS在分子遗传学方面的主要竞争优势是其对环境暴露的全面和累积评估。我们将集中在两个关键的曝光，社会经济地位（SES）和社会关系（SR），这构成了社会流行病学的发病率和死亡率的影响。我们围绕一个明确的基因通过环境方法建立我们的具体目标，以达到三个结果：情绪困扰，认知和炎症。在每一个（目标1至3）中，我们靶向主要遗传标记（即，那些在先前的研究中受到最大关注的人以及那些在潜在的神经生物学机制方面有功能原理的人），并检查SES和SR环境暴露作为其对结果影响的调节剂的作用。除了风险和保护调节因素，我们将重点关注累积SES劣势和累积SR优势。还将纳入一组额外的临时遗传标记物作为补充分析。拟议的工作将与MIDUS复习样本（新招募的受访者）和现有的纵向样本（通过环境假设测试关键基因的预计样本量为5，400名成年人）的成员一起进行。嵌入MIDUS中的还有一个全国性的双胞胎样本，将对这些样本进行额外的基因环境分析以及由双胞胎对照设计指导的分析。拟议研究的最终目标是从基于唾液的DNA提取中创建一个基因库，然后在拨款的最后两年举办研讨会，吸引来自全国各地的科学家讨论计划，以最佳方式利用该库在国家研究中的使用，以前所未有的深度评估各种环境暴露，其中只有两个在拟议的研究中进行了调查。总的来说，未来的科学调查，将产生于拟议的计划，使分子遗传学MIDUS是特殊的范围。

DESCRIPTION (provided by applicant): The central objective of the proposed research is to launch a new era of molecular genetics in a large national study of American adults, known as MIDUS (Midlife in the U.S.). Begun in 1995, MIDUS has become a major forum for multidisciplinary research on aging from early adulthood through later life, with a huge following from the scientific community (most frequently downloaded dataset at the national Archive of Computerized Data on Aging). Scientific productive from the study is extensive (about 400 publications), key themes of which clarify that the primary competitive advantage of MIDUS for molecular genetics is its comprehensive and cumulative assessments of environmental exposures. We will focus on two key exposures, socioeconomic status (SES) and social relationships (SR), which constitute well established influences on morbidity and mortality from social epidemiology. We build our specific aims around an explicit gene by environment approach to three outcomes: emotional distress, cognition, and inflammation. In each (Aims 1 through 3), we target primary genetic markers (i.e., those receiving the lion's share of attention in prior research as well as those for which there are functional rationales with regard to underlying neurobiological mechanisms) and examine the role of SES and SR environmental exposures as moderators of their influence on outcomes. Incorporating both risk and protective moderators, we will focus on cumulative SES disadvantage and cumulative SR advantage. An additional set of provisional genetic markers will also be included as supplemental analyses. The proposed work will be carried out with members of the MIDUS Refresher sample (newly recruited respondents) and the existing longitudinal sample (projected sample size for testing key gene by environment hypotheses is 5,400 adults). Embedded within MIDUS is also a national sample of twins for which additional gene by environment analyses will be conducted as well as analyses guided by a co-twin control design. A final aim of the proposed research is to create a genetic repository from the saliva-based DNA extraction and to then hold workshops in the final two years of the grant drawing on scientists from around the country to discuss plans to optimally leverage the use of this repository in a national study with unprecedented depth in assessment of diverse environmental exposures, only two of which are investigated in the proposed research. Overall, the future scientific inquiry that will emanate from the proposed plans to bring molecular genetics to MIDUS is of exceptional scope.