The current forward genetics of genome-wide association studies (GWAS) have successfully identified ~300 distinct loci regulating blood pressure (BP), primarily implicating sequence variation within the non-coding genome. However, for precision medicine of hypertension (HTN), a major challenge for public health, mechanistic identification of the genomic components altering the expression of BP genes is required. To solve this important bottleneck, we use a functional genomics inspired reverse genetics strategy to identify the transcription factors (TF), cis-regulatory elements (CRE), DNA variants and BP genes in four BP relevant tissues. Taking advantage of the analytical expertise and collaborations within the Family Blood Pressure Program Essential Hypertension GWAS consortium (FEHGAS3), and newly developed experimental and computational tools, we propose a novel framework for discovering the functional genetic modules, at identified BP loci and genome-wide, affecting inter-individual BP variation. Our approach enables answers to long-standing questions in BP genomics and physiology, with lessons for understanding many other complex diseases. We propose three major aims: (1) Identifying the transcription factors (TF), enhancers (CRE) and expressed genes in BP-relevant tissues; (2) Connecting enhancer (CRE) variation to gene expression and BP variation; and, (3) Identifying causal mechanisms that modulate BP to provide translational insights.
The major hypothesis explaining the results of blood pressure (BP) genome-wide association studies (GWAS) is that sequence variants at specific cis-regulatory elements (CRE or enhancer) affect the binding of their cognate transcription factors (TF) to alter expression of specific BP genes. In this second renewal of the FEHGAS consortium, we propose new computational and experimental approaches to identify the TFs, CREs, and target genes, active in four blood pressure target tissues, so that the effects of causal BP affecting genetic variation can be tested, within identified BP loci and genome-wide. This tissue-based view provides an alternative, complementary approach for understanding how BP variation leads to primary hypertension and hypertensive target organ damage, a major public health challenge.
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