Genetic Epidemiology of Cognitive Decline in an Aging Population Sample

描述（由申请人提供）：老年人的认知能力下降是一个巨大且日益严重的公共卫生问题。迄今为止，寻求识别负责任的遗传变异的认知功能下降的研究在很大程度上限于使用阿尔茨海默病的更极端的分类表型的连锁和候选基因关联研究。这些方法已经确定了几种罕见的和一种经过充分验证的常见风险等位基因，即APOE 4等位基因，但结果也显示出实质性的不一致。拟议工作的一个主题是，这种不一致性在很大程度上归因于这些研究中通常使用的设计，并且使用基于人群的研究的设计特征的方法可以补充现有的遗传研究。这些特征（足够的规模，严格和前瞻性的设计，以及来自特定地理区域的高比例适龄居民的参与）对于解构复杂疾病中发现的遗传和非遗传因素的混合物的努力特别相关。拟议的工作结合了布罗德研究所对人类基因组变异的杰出表征能力，以及两项纵向研究对认知衰退表型的丰富表征：来自认知衰退长期研究的探索性队列（宗教秩序研究或ROS）和来自严格人群研究的验证性样本（芝加哥健康与老龄化项目或ESTA）。这些研究的优势包括：（1）关于认知功能下降的现有纵向数据，（2）大多数受试者的DMA样本的可用性，（3）非遗传协变量的广泛记录，以及（4）对于确证性队列，一般人群的严格基础和50%非西班牙裔黑人和50%非西班牙裔白色白人的种族组成。建议对来自探索性队列的940名欧洲血统的人进行全基因组关联扫描（550，000个SNP），以确定与认知能力下降相关的基因座。使用根据与认知下降的关联强度选择的1500个SNP的组，将在来自确认性队列的1128名欧洲血统的人中验证探索性队列中发现的关联。将在来自确证性队列的1128名非洲裔美国人中评估经验证的等位基因，并对发现与欧洲裔美国人或非洲裔美国人受试者中的认知下降有效相关的等位基因进行精细定位。

DESCRIPTION (provided by applicant): Cognitive decline among older persons is a large and growing public health problem. To date, studies of decline in cognitive function seeking to identify the responsible genetic variants have been largely limited to linkage and candidate gene association studies using the more extreme categorical phenotype of Alzheimer's disease. These approaches have identified several rare and one well-validated common risk allele, the APOE ¿4 allele, but the results have also shown substantial inconsistency. A theme of the proposed work is that much of this inconsistency is attributable to the designs typically used in these studies, and that an approach using the design features of population-based studies can complement existing genetic studies. These features (adequate size, rigorous and prospective designs, and participation from a high proportion of age-eligible residents of a defined geographic area) are especially pertinent to efforts to deconstruct the mixture of genetic and non-genetic factors that is found in complex diseases. The proposed work combines outstanding ability to characterize variation in the human genome at the Broad Institute with the rich characterization of the cognitive decline phenotype from two longitudinal studies: an exploratory cohort from a long-term study of cognitive decline (the Religious Orders Study or ROS) and a confirmatory sample from a rigorous population study (the Chicago Health and Aging Project or CHAP). Advantages of these studies include: (1) existing longitudinal data on decline in cognitive function, (2) availability of DMA samples from most subjects, (3) extensive records of non-genetic covariates and, (4) for the confirmatory cohort, a rigorous base in the general population and an ethnic composition of 50% non- Hispanic black and 50% non-Hispanic white. It is proposed to conduct a genome-wide association scan (550,000 SNPs) in 940 people of European ancestry from the exploratory cohort to identify loci associated with cognitive decline. Using a panel of 1500 SNPs selected according to strength of association with cognitive decline, associations found in the exploratory cohort will be validated in the 1128 people of European ancestry from the confirmatory cohort. Validated alleles will be assessed in the 1128 African Americans from the confirmatory cohort and fine mapping will be conducted for alleles found to be validly associated with cognitive decline among European American or African American subjects.