Gene-based association study reveals a distinct female genetic signal in primary hypertension

Area of Science:

• Genetics
• Cardiovascular Disease Research
• Genomic Epidemiology

Background:

• Hypertension is a complex polygenic disease affecting over 1.2 billion adults globally.
• It is a significant risk factor for severe renal, cerebrovascular, and cardiovascular diseases.
• Despite high heritability, the genetic mechanisms of hypertension are not fully understood.

Purpose of the Study:

• To investigate the genetic underpinnings of essential (primary) hypertension using advanced gene-based association methods.
• To compare findings from genome-wide association studies (GWAS) with proteome-wide association studies (PWAS).
• To identify novel hypertension-associated genes and explore sex-specific genetic influences.

Main Methods:

• Utilized UK-Biobank data from European ancestry, including 74,090 hypertension cases and 200,734 controls.
• Employed proteome-wide association studies (PWAS) and compared results with variant-based genome-wide association studies (GWAS).
• Validated identified genes in independent cohorts, including the Finnish Biobank, and analyzed sex-specific genetic effects.

Main Results:

• Identified 70 statistically significant genes associated with hypertension via PWAS, many not found in GWAS.
• Validated 30% of PWAS-associated genes in independent cohorts.
• Discovered significant sex-dependent genetic effects, with a stronger genetic component in females for both hypertension and blood pressure traits.

Conclusions:

• Gene-based association methods offer improved interpretability for hypertension genetics compared to traditional GWAS.
• Identified genes are enriched in endothelial cells across multiple organs, suggesting a role in vascular health.
• The study highlights the clinical utility of understanding sex-dependent genetic effects in hypertension management.