EP6 - ECE_2007 - Genetic pleiotropy between primary aldosteronism and hypertension maps to adrenal cell states

Background Primary aldosteronism (PA) is a major yet underdiagnosed cause of secondary hypertension. While genome-wide association studies (GWAS) have identified genetic variants associated with PA and blood pressure (BP) separately, their shared genetic basis across multiple biological levels remains undefined. We aimed to systematically characterise the shared genetic architecture between PA and BP regulation, from pleiotropic loci and genes to pathways, and to integrate these findings with single-cell and spatial transcriptomic profiling of adrenal tissue. Methods We analysed genetic overlap between PA and BP using two independent PA datasets (French COMETE Network and Million Veteran Program) and three BP phenotypes (systolic, diastolic, and pulse pressure). Our stepwise analytic strategy included measuring genome-wide and regional genetic correlations, identifying shared risk loci through cross-trait meta-analysis, and prioritising candidate genes influencing both conditions. Biological relevance was evaluated using functional annotation, tissue-specific expression, and integrated single-cell and spatial transcriptomic analyses. Results PA demonstrated significant positive genetic correlations with all BP traits, with six specific genomic regions showing strong shared signals. We identified 143 independent loci associated with both PA and BP, predominantly in regulatory regions influencing gene expression across adrenal, vascular, cardiac, adipose, and neuroendocrine tissues. Gene-based analyses prioritised 43 shared genes, implicating pathways related to vascular remodelling and extracellular matrix turnover. Single-cell and spatial analyses revealed that SLC24A3 is highly expressed in aldosterone-producing adenoma cells and exhibits marked intratumoural heterogeneity. SLC24A3-positive regions corresponding to a functionally specialised, high secretory endocrine state, whereas SLC24A3-negative regions were characterised by a stress-adaptive, low-secretory state. Conclusions This study defines a shared genetic architecture linking PA and BP regulation. It demonstrates that their frequent clinical association arises not only from the direct haemodynamic effects of aldosterone but also from a substantial, pre-existing genetic predisposition that dysregulates common endocrine-vascular pathways.