Resistant hypertension (RH), in which blood pressure remains elevated on ≥3 medications or controlled on ≥4 medications, increases the risk of adverse cardiovascular events nearly 50% more than primary hypertension. We sought to identify genetic drivers of RH in a reliable and generalizable manner.

We utilized FinnGen (discovery) and UKBB (UK Biobank, replication) data sets to identify potential genetic drivers of RH. Using standard RH definitions, we developed cohorts in each data set and performed genome-wide (genome-wide association studies) and transcriptome-wide association studies, as well as Mendelian randomization analysis to evaluate potential causal associations.

We replicated 5 genetic loci in CASZ1, WNT2B, KCNK3, LSP1, and near the EVX1/EVX1AS locus for RH. Of these, CASZ1 and WNT2B are strongly associated with aldosterone homeostasis, while KCNK3 and LSP1 are associated with pathways mediating vasodilation. EVX1/EVX1AS are involved in mesendodermal lineage differentiation during gastrulation. Gene- and pathway-based analyses identified associations with vascular and cardiac developmental pathways in addition to aldosterone synthesis and secretion pathways. Transcriptome-wide association study analyses identified 37 genes, of which the genetically regulated expression is associated with RH, with particularly strong tissue-specific associations with KCNK3. Finally, Mendelian randomization identified possible causal association for 4 vascular risk factors (CRP [C-reactive protein]), triglycerides, waist circumference, and body mass index) with RH, with strong associations with identified lead variants.

We identified distinct genetic variants associated with RH, including those implicating the role of hyperaldosteronism, highlighting distinct pathways and targets for more effectively treating RH.