This study utilized UK Biobank data from 144 286 participants and employed whole-genome sequencing (WGS) data and time-to-event data over a 12-year follow-up period to identify susceptibility in genetic variants associated with hypertension. Following genotype quality control, 6 319 822 single nucleotide polymorphisms underwent analysis, revealing 31 significant variant-level associations. Among these, 29 were novel - 15 in Fibrillin-2 ( FBN2 ) and 4 in Junctophilin-2 ( JPH2 ). Mendelian randomization utilizing two identified variants (rs17677724 and rs1014754) suggested that a genetically induced decrease in heart FBN2 expression and an increase in adrenal gland JPH2 expression were causally linked to hypertension. Phenome-wide association (PheWAS) analysis using the FinnGen dataset confirmed positive associations of rs17677724 and rs1014754 with hypertension, assessed across 2727 traits in 377 277 individuals. Lastly, rs1014754 positively associated with kallistatin, whereas rs17677724 negatively associated with renin in the Fenland study, suggesting a counterregulatory response to high blood pressure. This study, employing WGS data, identified novel genetic loci and potential therapeutic targets for hypertension.
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