From GWAS loci to blood pressure genes, variants & mechanisms - Renewal

Defects in systolic (S) and diastolic (D) blood pressure (BP) regulation underlie clinical hypertension and its
subsequent target organ damage when unrecognized and untreated. Over the past 15 years, we have been major
contributors to the genomic analyses of BP enabling dissection of inter-individual SBP and DBP variation,
through this FEHGAS research program in collaboration with national/international consortia. While the
major approach has been to further expand GWAS, in this renewal (FEHGAS4), we introduce an alternative
novel program of using genome-cum-epigenome screens to quantify the contributions of each tissue and cell
type to causal BP variation through their transcription factors (TFs), cognate cis regulatory elements (CREs)
and target genes, organized into gene regulatory networks (GRNs). Our preliminary studies suggest significant
contributions by arterial-, heart-, adrenal- and kidney- specific regulatory variants in decreasing order. In this
proposal we ask: (1) Which tissues and cell types contribute to SBP and DBP variation between humans? (2)
Which genes in a tissue/cell type contribute to human SBP and DBP control? (3) What is the functional
architecture of inter-individual SBP and DBP variation? (4) What is the differential tissue contribution to risk.
1

Grant Number: 5R01HL086694-15
NIH Institute/Center: NIH
Principal Investigator: ARAVINDA CHAKRAVARTI