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，在理解疾病遗传基础方面的大部分进展依赖于对基因组数据的计算分析。对于这项分析来说，一些最有用的数据是人类变异数据。这些数据包括一组个体与疾病相关的基因变异的信息。了解变异和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。这一挑战跨越了三个研究领域：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座上的功能变异，以及功能变异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哪些亚型是不同药物反应的候选者。 在这个提案中，我们概述了我们解决这个问题的方法，并建议建立工具来模拟基因位点变异的功能，将中间表型与疾病结局相关联，并基于遗传变异识别疾病的亚型。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。我们展示了关于嗜铬粒蛋白A基因座的初步结果。这项提案的疾病焦点是高血压，这些工具将应用于通过药物基因组学项目在加州大学圣迭戈分校收集的大量数据。 这份提案包含了对Eleazar Ekin的广泛培训计划，包括在加州大学圣迭戈分校的课程，以便他为该项目获得必要的高血压和遗传学背景。丹尼尔·奥康纳和尼古拉斯·肖克将在整个项目中指导Eleazar。这种培训和指导将使Eleazar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，因为它试图了解个人的基因变异与疾病后果之间的关系。识别与复杂疾病有关的变异是最终目标的第一步，即根据个人的遗传特征量身定制治疗方法。

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.