Unraveling the hidden link: neuroticism as a risk factor for upper urinary tract calculi-insights from Mendelian randomization analysis.

Background: Upper urinary tract calculi (UUTC) are major risk factors for renal insufficiency and nephrectomy with psychological distress, notably depression and anxiety, being common among affected patients. Depression and anxiety are associated with heightened neuroticism. Individuals with neuroticism frequently exhibit a range of urological disorders. Given the limited research on UUTC and neuroticism, this study aims to explore this relationship using Mendelian randomization (MR) analysis.

Methods: We assessed the effects of neuroticism and associated psychological traits on UUTC using a two-sample MR approach, primarily employing the inverse variance weighted (IVW) method, with additional analysis via MR-Egger and weighted median methods. To ensure robustness, we conducted sensitivity analyses using Cochran's Q test, MR-Egger intercept, and MR-pleiotropy residual sum and outlier (PRESSO). At the same time, we selected the neuroticism score for verification queue of the exposure. Furthermore, to explore the independent effects of neuroticism traits on UUTC, we performed multivariable MR analyses on phenotypes with no pleiotropy, IVW P values below 0.05, and consistent directions across all three MR methods.

Results: Our MR analysis revealed a significant causal impact of neuroticism on UUTC using the IVW [odds ratio (OR) =1.15, 95% confidence interval (CI): 1.02 to 1.29, P=0.03) and weighted median (OR =1.22, 95% CI: 1.03 to 1.44, P=0.02) methods. Verification queue similarly confirmed that the neuroticism score was a risk factor for UUTC (IVW, OR =1.11, 95% CI: 1.03 to 1.19, P=0.007). Sensitivity analyses indicated no heterogeneity or pleiotropy. Additionally, IVW analyses identified experiencing mood swings (OR =1.41, P=0.047), feeling lonely (OR =6.03, P<0.001), and feeling worry (OR =1.58, P=0.03) as significantly associated with UUTC. Multivariate MR analysis showed that experiencing mood swings is a stand-alone risk factor for UUTC (OR =1.75, P=0.03).

Conclusions: Our MR analysis has pinpointed neuroticism as a risk factor for UUTC, with experiencing mood swings identified as an independent risk factor for UUTC, offering new insights into the brain-kidney connection. The exact pathways driving this relationship require further study. These results highlight the necessity of vigilant urinary stone surveillance in individuals exhibiting neurotic traits.