Genome-Wide Association Analysis in Essential Hypertension (FEHGAS study)

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DESCRIPTION (provided by applicant): Essential hypertension is a leading cause of disease morbidity and mortality at great societal cost. Despite multiple treatment options, the pathophysiology of this complex heritable trait is largely unknown although we have made some progress in understanding its genetic determinants through the multi-center Family Blood Pressure Program (FBPP). We now propose an efficient SNP (single nucleotide polymorphism) based genome wide association study to comprehensively identify hypertension genes using the population-based Atherosclerosis Risk in Communities (ARIC) and the family-based FBPP studies. We name this study FEHGAS (FBPP-ARIC Essential Hypertension Genome-Wide Association Study). In ARIC, we will identify genes affecting blood pressure (BP) extremes, and then validate the findings in FBPP hypertensives across different risk factors. Our experimental approach will stratify the initial search by populations (African American vs. European American) but consider separate gender effects. Our analysis will specifically test for gene-gene and gene environment interactions. Additionally, we will assess the contribution of genomic copy number (dosage) polymorphisms in essential hypertension based on the signal intensity of the SNP data. To buttress our findings, we will compare our results to those from a random sample from ARIC (funded elsewhere) and the NHLBI-funded Framingham SHARe project. Our short-term goal is to identify genetic determinants of essential hypertension that might lead to novel pharmacologic targets. The long-term goal of this study is to enable a molecular understanding of the genetic basis of essential hypertension and provide a paradigm for SNP-based gene discovery in complex human disease.