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.
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