Discovering the Genetic Basis of Hypertension

描述（由申请人提供）： 随着人类基因组计划的完成，理解疾病遗传基础的大部分进展依赖于对基因组数据的计算分析。对这种分析最有用的一些数据是人类变异数据。该数据包括与一个个体群体的疾病相关的基因变异的信息。了解变异与疾病之间的关系是一个根本性的挑战，它可以揭示人类疾病的遗传基础和机制。这项挑战跨越三个研究领域：遗传学，生物信息学和医学。了解疾病的遗传基础包括两个步骤。首先，我们必须确定与疾病相关的每个基因位点的功能变体以及功能变体对基因调控和基因产物的影响。其次，我们必须了解这些中间表型如何影响疾病结果。利用这些信息，我们可以确定疾病的亚型，这些亚型是不同药物反应的候选者。 在这个建议中，我们概述了我们的方法，这个问题，并建议建立工具，用于建模的功能，在基因位点的变化，相关的中间表型疾病的结果和识别亚型的疾病的基础上遗传变异。我们方法的核心涉及单倍型分析，我们利用以前开发的工具进行这种分析。我们展示了嗜铬粒蛋白A基因座的初步结果。该提案的疾病重点是高血压，这些工具将通过药物基因组学项目应用于UCSD收集的大量数据。 该提案包含针对Eleazar Eskin的广泛培训计划，包括加州大学圣地亚哥分校的课程，以便他获得该项目所需的高血压和遗传学背景。丹尼尔奥康纳和尼古拉斯肖克将指导以利亚撒在整个项目。这种培训和指导将使以利亚撒能够使他的研究在医学上产生更大的影响。 这项研究与公共卫生有关，因为它试图了解个体遗传变异与疾病结果之间的关系。识别复杂疾病中涉及的变异是根据个体遗传学定制治疗最终目标的第一步。

DESCRIPTION (provided by applicant): With the completion of the human genome project, much of the progress in understanding the genetic basis of disease relies on computational analysis of genomic data. Some of the most useful data for this analysis is human variation data. This data consists of information on the variation in genes associated with a disease for a population of individuals. Understanding the relation between variation and disease is a fundamental challenge, which can shed light on the genetic basis and mechanisms of human disease. This challenge spans three research fields: genetics, bioinformatics and medicine. Understanding the genetic basis of disease involves two steps. First, we must determine the functional variants in each gene locus that is linked to the disease and the effect of functional variants on the regulation and gene products of the gene. Second, we must understand how these intermediate phenotypes affect disease outcomes. Using this information, we can identify subtypes of the disease which are candidates for different drug response. In this proposal we outline our approach for this problem and propose to build tools for modeling the function of variation in a gene locus, correlating the intermediate phenotypes to disease outcomes and identifying subtypes of the disease based on genetic variants. The core of our approach involves haplotype analysis and we leverage previously developed tools for this analysis. We demonstrate initial results over the Chromogranin A locus. The disease focus of this proposal is hypertension and the tools will be applied to the large amount of data collected at UCSD through the pharmacogenomics project. This proposal contains of an extensive training plan for Eleazar Eskin including courses at UCSD in order for him to obtain the necessary background in hypertension and genetics for the project. Daniel O'Connor and Nicholas Schork will mentor Eleazar throughout the project. This training and mentoring will put Eleazar in a position to have his research have a larger impact in medicine. This research is relevant to public health because it attempts to understand the relation between an individual's genetic variation and disease outcomes. Identification of the variants that are implicated in complex disease is the first step in the ultimate goal of tailoring treatments to an individual's genetics.