Gene-Environment Interaction in Cognition in Venezuelan Families

委内瑞拉家庭认知中的基因与环境相互作用

基本信息

批准号：
8690728
负责人：
Inara Chacon
金额：
$ 57.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8690728
关键词：
Academic Medical Centers Address Admixture Affect Alzheimer&apos s Disease Award Blood Platelets Blood Pressure Brain Diseases Cardiovascular system Caribbean region Caring Chromosome Mapping Clinical Cognition Cognitive Collaborations Communities Complex Country DNA Data Dementia Developed Countries Developing Countries Disease Early Diagnosis Economic Burden Economics Elderly Environmental Risk Factor Extended Family Family Family Study Gene Targeting Genes Genetic Genomics Goals Grant Health Personnel Healthcare Heritability Heterogeneity High Prevalence Image Inbreeding Incidence Income Individual Joints Latin America Life Magnetic Resonance Imaging Measures Memory Microvascular Dysfunction Molecular Neuropsychology Nucleotides Patients Performance Phenotype Polymorphic Microsatellite Marker Population Population Genetics Predisposition Prevention program Proteins Protocols documentation Public Health Quantitative Trait Loci Research Research Infrastructure Research Training Resolution Resources Risk Factors Role Rosa Scientist Stroke Surrogate Markers Techniques Technology Training Programs Universities Validation Vascular Dementia Venezuela White Matter Hyperintensity Work age related base cardiovascular risk factor cohort comparative density disability experience follow-up gene environment interaction gene therapy genetic linkage analysis genetic variant genome wide association study genome-wide analysis genome-wide linkage improved member mortality neuroimaging novel population based post stroke prevent research study response skills training social tool trait

项目摘要

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.

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庭的正常功能，给发达国家和发展中国家（包括委内瑞拉）带来了巨大的社会、经济和公共卫生负担。然而，痴呆症的许多根本原因仍有待确定和理解。缺血性小血管病（SVD）是血管性痴呆的主要原因，也是阿尔茨海默病的主要原因。研究表明，神经影像学中的白质高信号 (WMH) 可用于评估亚临床和临床 SVD。 WMH 表型很复杂，其原因尚不清楚。 WMH 具有高度遗传性（55-83%）；然而，之前的研究未能鉴定出导致 WMH 表型的基因，可能是因为 WMH 受到多种遗传变异的影响，且效应量较小；受多种环境风险因素影响；或他们的互动。为了规避上述一些问题，我们建议研究居住在委内瑞拉马拉开波湖的一个高度近亲繁殖的大家庭。在这个独特的同质群体中，遗传和环境异质性将被最小化，从而降低复杂性。利用这个队列，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；心血管和人口统计学危险因素，以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（目标 1）。随后，我们将估计遗传力。对于高度遗传性状，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系的全基因组关联研究，以识别可能有助于WMH表型的遗传变异（目标2）。该基因图谱实验中的顶级 SNP 将在圣卢西亚附近独立社区的老年人身上进行复制，过去十年来，PI 使用相同的临床和成像方案对这些老年人进行了研究。为了实现这些目标，我们建立了一支在基因组学、神经影像学和委内瑞拉人口方面拥有丰富经验的科学家团队。除了科学目标外，我们还将提高当地的研究能力以及识别和为快速增长的老年人口提供护理的能力（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症的新方法。