Genetic evidence linking circadian rhythm genes and hypertension: A two-sample Mendelian randomization study

Abstract

Objectives Circadian rhythms regulate human health, and observational studies have linked their disruption to hypertension; however, confounding factors and reverse causality limit causal interpretation. We aimed to evaluate the existing evidence linking circadian gene sets and hypertension using Mendelian randomization. Methods Two-sample Mendelian randomization was performed using genome-wide association study summary-level data from non-overlapping European ancestry samples. Genetic variants of 1276 circadian genes (CGDB) were instrumental variables; the outcome was hypertension genome-wide association study data from the UK Biobank (ieu-b-5144; 463,010 participants). Single nucleotide polymorphisms were selected at p<5 × 10−8 (mean F-statistic: 276.5). Inverse variance weighting was the primary method used. Benjamini–Hochberg false discovery rate correction was applied across all 1276 genes. Sensitivity analyses were performed using heterogeneity testing, Mendelian randomization–Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, Steiger directionality testing, and leave-one-out analyses. Results Mendelian randomization identified 39 nominally significant associations (inverse variance weighting, p < 0.05). After false discovery rate correction, four genes reached statistical significance: PHOSPHO1 (odds ratio = 0.988, 95% confidence interval: 0.983–0.993), BAIAP3 (odds ratio = 1.009, 95% confidence interval: 1.005–1.014), OSGIN2 (odds ratio = 0.990, 95% confidence interval: 0.986–0.995), and ZDHHC18 (odds ratio = 1.012, 95% confidence interval: 1.007–1.018). The remaining nominal associations did not survive false discovery rate correction and were classified as exploratory. Functional enrichment implicated circadian rhythm, apoptosis, and glycosaminoglycan biosynthesis pathways. Sensitivity analyses did not reveal significant heterogeneity or pleiotropy. Conclusions These findings are hypothesis-generating and require experimental validation. PHOSPHO1, BAIAP3, OSGIN2, and ZDHHC18 demonstrated statistically significant associations with hypertension risk after false discovery rate correction and should be prioritized for follow-up. Other nominal findings should be interpreted as exploratory.