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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Luo, James
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Rudra, Pratyaydipta; Broadaway, K Alaine; Ware, Erin B et al. (2018) Testing cross-phenotype effects of rare variants in longitudinal studies of complex traits. Genet Epidemiol 42:320-332
Lee, Dongwon; Kapoor, Ashish; Safi, Alexias et al. (2018) Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants. Genome Res 28:1577-1588
Ashar, Foram N; Mitchell, Rebecca N; Albert, Christine M et al. (2018) A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. Eur Heart J 39:3961-3969
Prins, Bram P; Mead, Timothy J; Brody, Jennifer A et al. (2018) Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biol 19:87
Keaton, Jacob M; Gao, Chuan; Guan, Meijian et al. (2018) Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans. Genet Epidemiol 42:559-570
Fernández-Rhodes, Lindsay; Malinowski, Jennifer R; Wang, Yujie et al. (2018) The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis. PLoS One 13:e0200486
Weng, Lu-Chen; Guan, Weihua; Steffen, Lyn M et al. (2018) Pleiotropic effects of n-6 and n-3 fatty acid-related genetic variants on circulating hemostatic variables. Thromb Res 168:53-59
Hong, Jaeyoung; Hatchell, Kathryn E; Bradfield, Jonathan P et al. (2018) Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations. J Clin Endocrinol Metab 103:1380-1392
Loomis, Stephanie J; Li, Man; Maruthur, Nisa M et al. (2018) Genome-Wide Association Study of Serum Fructosamine and Glycated Albumin in Adults Without Diagnosed Diabetes: Results From the Atherosclerosis Risk in Communities Study. Diabetes 67:1684-1696
Gong, J; Nishimura, K K; Fernandez-Rhodes, L et al. (2018) Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. Int J Obes (Lond) 42:384-390

Showing the most recent 10 out of 332 publications