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

Abstract

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.

Keywords: FinnGen; Mendelian randomization (MR); Neuroticism; psychological traits; upper urinary tract calculi (UUTC).

Figure 1

Three hypotheses for a two-sample Mendelian randomization study and multivariate MR analysis include psychological traits that show no pleiotropy, have IVW P values below 0.05, and display consistent effects across all three MR methods. SNP, single nucleotide polymorphism; MR, Mendelian randomization; UUTC, upper urinary tract calculi; MVMR, multivariate Mendelian randomization; IVW, inverse variance weighted.

Figure 2

Results of the two-sample MR analysis and sensitivity analysis. GWAS ID, genome-wide association study identifier; IVW, inverse variance weighted; MR, Mendelian randomization; nsnp, number of single nucleotide polymorphisms; P, the P values of the IVW, MR-Egger, and weighted median methods; OR, odds ratio; CI, confidence interval; Q, Q-value of the Q test; Q_df, Q statistic degrees of freedom; Q_P, Q statistic P value; Int.P, the P value of intercept.

Figure 3

Results of the multivariable MR analysis. GWAS ID, genome-wide association study identifier; nsnp, number of single nucleotide polymorphisms; OR, odds ratio; CI, confidence interval.