Genetic Insights into the Therapeutic Targets for Essential Hypertension: Mendelian Randomization and Colocalization Analysis

The prevalence of Essential Hypertension (EH) is increasing globally, and the effectiveness of pharmacological treatments remains far from ideal. Combining Mendelian Randomization (MR) to identify potential drug targets may be key to reducing the disease burden and developing potential treatments. We utilized the UK Biobank cohort (ncase = 54358, ncontrol = 408652) to extract summary statistics for EH and further validated in the FinnGen cohort (ncase = 92462, ncontrol = 265626). Cis-expression quantitative trait loci (cis-eQTL) from available druggable genes were retrieved and used as genetic instrumental variables. Two-sample MR analysis and colocalization analysis were conducted to examine whether identified genes and EH share variants, further consolidating MR results. Ten drug targets (FES, SLC22A4, PTK2B, BLK, ITPR1, NEGR1, GRK4, ADM, MAPK3, MAST3) showed significant MR results in two independent datasets, with no reverse causation observed. Colocalization analysis indicated that FES (PP.H4 = 0.99) and SLC22A4 (PP.H4 = 0.82) shared the same variants with EH, providing strong evidence. Additionally, FES showed significant associations with reduced risk of coronary artery disease, systolic blood pressure, and diastolic blood pressure, while SLC22A4 was significantly associated with increased diastolic blood pressure. Our results suggest that targeting FES and SLC22A4 might treat or cause EH, potentially revealing new pathophysiological pathways and treatment targets for EH.