Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension

Objective: Apparent treatment-resistant hypertension (aTRH) is associated with adverse outcomes compared with mild hypertension. However, the etiopathogenesis of aTRH is still poorly elucidated and only a handful of genetic discovery efforts in aTRH with small sample sizes and largely null results have been described. Design and method: We conducted a genome-wide association analysis in 55733 hypertensive individuals with a register-based diagnosis of hypertension from the FinnGen study. Cases included 39737 individuals with aTRH (use of four or more antihypertensives over life course) and controls included 15996 individuals with mild hypertension (maximum use of one antihypertensive over life course). Top variants associated with aTRH at p<5.0e-8 were tested for replication in up to 36461 hypertensive participants of UK Biobank. aTRH-risk loci were characterised using pathway enrichment, a transcriptome-wide association study (TWAS), and mendelian randomization (MR). Results: The analysis found six genome-wide significant associations that also replicated in UK Biobank, all of which have been previously associated with BP. These loci were identified in the proximity of genes involved in mineralocorticoid receptor activity (WNT2B [odds ratio 1.21; p=6.9e-25], CASZ1 [odds ratio 1.14; p=2.7e-48]), endothelial function (LSP1 [odds ratio 1.13; p=2.0e-18], HOTTIP [odds ratio 1.28; p=2.4e-25]), and ion transport (KCNK3 [odds ratio 0.88; p=7.9e-19], SLC4A7 [odds ratio 0.89; p=1.1e-17]). VEGAS2 pathway analysis revealed significant enrichment of aTRH-risk loci in pathways involved in vitamin B12 metabolism and negative regulation of catabolic processes. In transcriptome-wide association studies using TWAS-Fusion and eQTL based on RNA-sequencing analyses in different tissues, we identified 37 genes of which the genetically regulated expression is associated with aTRH at the transcriptome-wide level and colocalized in at least one tissue (22 genes in arteries and heart; 13 genes in subcutaneous or visceral adipose tissue; 11 genes in adrenal gland). Of these genes, two overlapped with the six genome-wide significant aTRH-risk loci. Using two-sample MR, we found evidence for a possible causal association for four vascular risk traits (CRP, triglycerides, waist circumference, and BMI) with aTRH. Conclusions: Our results provide critical insights to inform future biological research on aTRH pathogenesis and highlight potential drug targets for intervention.