Polyuria, characterized by increased 24-hour urine output, is a key pathophysiological contributor to nocturia. While obesity is an established risk factor for nocturia, its causal relationship with polyuria specifically remains unclear due to potential confounding and reverse causation in observational studies. We aimed to assess the causal effect of body mass index (BMI) on polyuria using Mendelian randomization (MR), and to investigate potential mediation via fatty acids and sleep traits.

We conducted a two-sample MR study using publicly available genome-wide association study (GWAS) summary statistics. Genetic instruments for BMI were obtained from UK Biobank. Single-nucleotide polymorphisms (SNPs) strongly associated with BMI (P<5 × 10-8) were selected as instrumental variables. Summary statistics for polyuria were sourced from UK Biobank and FinnGen. For mediation analysis, genetic associations with fatty acids (total fatty acids, omega-3 fatty acids, omega-6 fatty acids, saturated fatty acids, monounsaturated fatty acids and polyunsaturated fatty acids) were obtained from metabolomics GWAS within UK Biobank. Genetic instruments for six sleep traits (daytime sleepiness, chronotype, insomnia, napping, obstructive sleep apnea, sleep duration) were derived from large-scale GWAS meta-analyses. The primary causal estimate was calculated using inverse-variance weighted (IVW) method. Sensitivity analyses included weighted median, MR-Egger, simple mode and weighted mode. Two-step MR mediation analysis was performed to identify potential mediators; an indirect effect was considered suggestive if both the exposure–mediator and mediator–outcome associations were significant (P < 0.05) in at least one robust method.

Genetically predicted higher BMI was positively associated with increased risk of polyuria in UK Biobank (IVW OR=1.001, 95% CI 1.0002–1.002, P=0.008). Sensitivity analyses yielded directionally consistent estimates.
For mediation, BMI was significantly associated with all six fatty acid traits and all six sleep traits (all P < 0.05). In the mediator–outcome analysis, four mediators showed suggestive associations with polyuria in FinnGen:
①Omega-3 fatty acids (MR-Egger OR=1.187, 95% CI 1.022–1.377, P=0.029);
②Insomnia (IVW OR=3.100, 95% CI 1.640–5.862, P<0.001);
③Napping (IVW OR=2.285, 95% CI 1.161–4.500, P=0.017);
④Sleep duration (IVW OR=1.555, 95% CI 1.006–2.405, P=0.047).
Other fatty acids and sleep traits showed no significant association with polyuria. These results suggest that omega-3 fatty acids, insomnia, napping, and sleep duration may mediate the pathway from obesity to polyuria.

Our MR analysis provides genetic evidence supporting a causal effect of higher BMI on polyuria risk. The mediation findings suggest that omega-3 fatty acid metabolism and multiple sleep traits—particularly insomnia, napping, and sleep duration—may partially mediate this pathway. These findings may reflect disrupted circadian rhythms in obese individuals and highlight potential mechanistic links between obesity and polyuria through both metabolic and sleep-related pathways. However, it is important to note that our study directly assessed polyuria, not nocturia. While polyuria is a major contributor to nocturia, the findings cannot be directly extrapolated to nocturia without further validation. Nocturia is a multifactorial condition involving nocturnal polyuria, global polyuria, reduced bladder capacity, and sleep disorders, which our study did not fully capture. Therefore, the causal relationship between BMI and nocturia remains to be established.

This MR study demonstrates that genetically predicted obesity causally influences polyuria risk, potentially mediated by omega-3 fatty acid metabolism and by sleep traits—particularly insomnia, napping, and sleep duration. These findings underscore the importance of weight management and sleep health in preventing polyuria-related lower urinary tract symptoms. Further research with refined phenotyping of polyuria subtypes and larger GWAS samples for nocturia and mediators is warranted to confirm these observations.