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全国性研究中启动分子遗传学的新时代，称为MIDUS（美国的中年）。从1995年开始，MIDUS已经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数据档案馆）。该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。我们将重点关注两个关键因素，社会经济地位（SES）和社会关系（SR），它们构成了社会流行病学对发病率和死亡率的既定影响。我们通过环境方法围绕显性基因构建我们的特定目标，以获得三种结果：情绪困扰、认知和炎症。在每个（目标1至目标3）中，我们针对主要遗传标记（即那些在先前研究中受到最大关注的标记，以及那些在潜在神经生物学机制方面具有功能基础的标记），并检查SES和SR环境暴露作为其对结果影响的调节因子的作用。结合风险和保护性调节因子，我们将重点关注累积的SES劣势和累积的SR优势。另外一组临时遗传标记也将作为补充分析。拟议的工作将在MIDUS Refresher样本（新招募的受访者）和现有的纵向样本（根据环境假设测试关键基因的预计样本量为5400名成年人）的成员中进行。MIDUS还包含一个全国双胞胎样本，将通过环境分析对其进行额外的基因分析，并在双胎控制设计的指导下进行分析。拟议研究的最终目的是建立一个基于唾液的DNA提取的遗传资源库，然后在拨款的最后两年举行研讨会，邀请来自全国各地的科学家讨论在评估不同环境暴露方面具有前所未有深度的国家研究中最佳利用该资源库的计划，其中只有两种在拟议的研究中进行了调查。总的来说，未来的科学研究将从拟议的计划中产生，将分子遗传学引入MIDUS是一个特殊的范围。

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.