Gene-Environment Interaction in Cognition in Venezuelan Families

描述（由申请人提供）：与年龄相关的痴呆症扰乱了患者及其家人的正常功能，给包括委内瑞拉在内的发达国家和发展中国家带来了重大的社会、经济和公共卫生负担。然而，痴呆症的许多潜在原因仍有待确定和了解。缺血性小血管疾病（SVD）是血管性痴呆的主要原因，也是阿尔茨海默病的主要诱因。研究表明，神经影像学白质高信号（WMH）可用于评估亚临床和临床SVD。WMH表型是复杂的，其原因尚不清楚。WMH具有高度遗传性（55-83%）；然而，以前的研究尚未能够确定导致WMH表型的基因，这可能是因为WMH受多种影响较小的遗传变异的影响；多重环境风险因素；或者它们的相互作用。为了避免上述一些问题，我们建议研究一个高度近亲繁殖的大家庭，居住在委内瑞拉的马拉开波湖。在这个独特的同质群体中，遗传和环境的异质性将被最小化，从而降低了复杂性。通过这一队列，我们将获得一套全面的表型和危险因素数据，包括表征亚临床和临床SVD的神经影像学；心血管和人口危险因素，了解这些因素如何影响WMH；和神经心理学电池来评估认知表现（目的1）。随后，我们将估计遗传力。对于高遗传性状，我们将使用高密度2.5M SNP芯片进行全基因组连锁研究和基于家族的全基因组关联研究，以确定可能导致WMH表型的遗传变异（目标2）。从基因定位实验中获得的顶级snp将在圣卢西亚附近的一个独立的社区居住的老年人身上复制，过去十年来，PI一直在使用相同的临床和成像协议对他们进行研究。为了实现这些目标，我们建立了一个在基因组学、神经成像和委内瑞拉人口方面具有丰富经验的科学家团队。除了科学目标外，我们将提高本地的研究能力，以及认识和照顾迅速增长的老年人口的能力（目标3）。该项目将从根本上有助于理解SVD的机制，进而确定预测、预防和有效治疗与年龄相关的痴呆的新方法。

DESCRIPTION (provided by applicant): Age-related dementia disrupts normal functioning of afflicted individuals and their families, imposing significant social, economic, and public health burdens in both developed and developing countries, including Venezuela. Yet many of the underlying causes for dementia remain to be identified and understood. Ischemic small vessel disease (SVD) is a leading cause of vascular dementia and a major contributor to Alzheimer's disease. It has been shown that white matter hyperintensities (WMH) from neuroimaging can be used to evaluate subclinical and clinical SVD. The WMH phenotype is complex, and its causes are not well known. WMH is highly heritable (55-83%); yet, previous studies have not been able to identify genes that contribute to the WMH phenotype, probably because WMH is affected by multiple genetic variants with small effect sizes; by multiple environmental risk factors; or their interactions. To circumvent some of the aforementioned problems, we propose to study one highly inbred, extended family, residing in Lake Maracaibo, Venezuela. In this uniquely homogenous population, genetic and environmental heterogeneity will be minimized, and thus the complexity reduced. Using this cohort, we will obtain a comprehensive set of phenotype and risk factor data, including neuroimaging to characterize subclinical and clinical SVD; cardiovascular and demographic risk factors to understand how these factors may influence WMH; and neuropsychology battery to assess cognitive performance (Aim 1). Subsequently, we will estimate heritability. For the highly heritable traits, we will perform genome wide linkage study and family based genome wide association study using a high density 2.5M SNP chips to identify genetic variants that may contribute to the WMH phenotype (Aim 2). The top SNPs from this gene mapping experiments will be replicated in an independent, nearby community-dwelling elderly in Santa Lucia, who have been studied for the past decade by the PI, using the same clinical and imaging protocols. To accomplish these goals, we have build a team of scientists with extensive experience in genomics, neuroimaging, and Venezuelan populations. In addition to the scientific aims, we will enhance the local research capacity along with the ability to recognize and provide care for a rapidly growing population of elderly (Aim 3). This project will contribute fundamentally to the understanding of the mechanisms responsible for SVD, and in turn, identify new means to predict, prevent and effectively treat age-related dementia.