GWAS for Defining the Pathogenesis of Hypertension: Have They Delivered?

Area of Science:

• Genetics
• Cardiovascular Disease Research

Background:

• Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) and loci associated with hypertension.
• However, most SNPs have small effect sizes, and their causal roles in hypertension remain largely unverified experimentally.
• There is a critical need for methods to prioritize these genetic findings for effective hypertension research.

Purpose of the Study:

• To propose and outline novel approaches for prioritizing genetic variants associated with hypertension.
• To move beyond simple association lists towards identifying key mediators of hypertension pathophysiology.

Main Methods:

• Integrating genome-wide association study (GWAS) data with multiomic datasets (proteomics, transcriptomics, epigenomics).
• Utilizing linked clinical and genetic data to analyze hypertension subphenotypes with distinct genetic drivers.
• Performing whole exome/genome sequencing in severe hypertension cohorts to identify rare, high-effect variants.

Main Results:

• The proposed methods aim to enhance the identification of causal genetic factors for hypertension.
• These approaches are designed to yield a more focused set of high-relevance genetic loci and SNPs.
• The focus is on understanding the underlying pathophysiology rather than simply expanding association lists.

Conclusions:

• Advanced integration of multiomic, clinical, and sequencing data is crucial for prioritizing hypertension-associated genetic variants.
• These refined strategies will facilitate the identification of key genetic mediators of hypertension.
• The proposed methods offer a path to uncover the causal underpinnings of hypertension pathophysiology.