Genetic Analysis of Primary Aldosteronism Bridging Disease Subtypes and the Phenotypic Continuum

Primary aldosteronism (PA) is a common cause of secondary hypertension. To investigate its genetic basis, we perform a trans-ancestry genome-wide association study (GWAS) meta-analysis, with subtype-specific analyses for aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). Subsequently, we conduct genetic mediation analysis to partition PA effects on cardiovascular outcomes into blood pressure (BP)-mediated and BP-independent components. We further use a genetic risk score (GRS) to assess whether polygenic susceptibility to PA is associated with aldosterone-related traits in both population-based and PA case cohorts. We report 19 PA loci, including 13 new loci. While PA shares a broad polygenic framework across ancestries, subtype-specific heterogeneity exists, most notably at TARID/TCF21, which is preferentially associated with APA. A substantial proportion of the association between PA and cardiovascular disease is independent of systolic BP, particularly for heart failure and ischemic stroke. In population-based cohorts, a higher PA GRS is associated with higher systolic BP, lower serum potassium, and higher aldosterone levels, whereas in PA cases, particularly BAH, a higher GRS is linked to more severe aldosterone excess. Our results suggest that subclinical autonomous aldosterone excess exists along a continuous genetic spectrum across the population and that PA drives cardiovascular disease through substantial BP-independent pathways.