Investigating the causal relationship between insomnia and ovarian cancer risk: a Mendelian randomization study

The epidemiological association between insomnia and ovarian cancer remains controversial, as observational studies are inherently susceptible to confounding factors and reverse causation bias. While neuroendocrine dysregulation may contribute to the pathogenesis of hormone-sensitive malignancies, there is a paucity of genetic evidence supporting a causal relationship between sleep disturbances and ovarian carcinogenesis.

We conducted a two-sample Mendelian randomization analysis using summary-level genetic data obtained from separate genome-wide association studies (GWAS) of insomnia and ovarian cancer in European populations. The inverse-variance weighted (IVW) method served as our primary analytical approach, with complementary validation through MR-Egger regression, weighted median estimation, and MR-PRESSO sensitivity analyses. Instrumental variables were stringently selected based on genome-wide significance (P < 5 × 10⁻⁸), linkage disequilibrium thresholds (r² < 0.001), and instrument strength quantification using F-statistics , with all retained SNPs demonstrating strong instrument validity (F > 30). Horizontal pleiotropy was systematically evaluated through Egger intercept testing and MR-PRESSO outlier correction procedures.

The IVW method found a statistically significant but clinically marginal association between insomnia and ovarian cancer risk (OR = 1.00, 95%CI: 1.00-1.01, p= 0.02). Nonetheless, both the MR-Egger analysis (OR = 1.00, 95%CI: 0.99-1.01, p= 0.68) and the weighted median analysis (OR = 1.00, 95%CI: 0.99-1.01,p= 0.21) produced non-significant results. The instruments are strong (mean F-statistic = 38.8). No evidence of horizontal pleiotropy or heterogeneity was found (MR-PRESSO p= 0.731; Egger intercept p= 0.986; Cochran's Q p= 0.643).

The study reveals a modest association between insomnia and ovarian cancer incidence, though this relationship demonstrates limited clinical relevance. Genetic analyses indicate that insomnia does not independently contribute to elevated ovarian cancer risk.