Fig. 3: Mediation analysis of the effect of GLP-1R expression in pancreas on endometrioid ovarian cancer through metabolic factors.

a Phenome-wide association scan for endometrioid ovarian cancer. The Manhattan plot displays associations between genetic instruments for GLP-1R expression and 2204 phenotypes, categorized by domain. The y-axis shows the strength of association (−log₁₀ P value) based on Mendelian randomization analysis results from EpiGraphDB. Red and blue horizontal lines indicate false discovery rate (FDR) thresholds of P-value < 0.05 and the genome-wide significance level (P-value < 5 × 10⁻⁸), respectively. b Schematic of significant mediators in the GLP-1R–endometrioid ovarian cancer pathway. The diagram summarizes mediators identified through two-step MR analysis, showing the proportion mediated for each. All mediated proportions were statistically significant after FDR correction (P-value < 0.05). c Association of candidate mediators with ovarian cancer histotypes. Forest plot displays MR estimates for six mediators—body mass index, waist circumference, hip circumference, arm fat mass, arm predicted mass, and 18:2 linoleic acid—across five ovarian cancer subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), mucinous (MOC), endometrioid (ENOC), and clear cell (CCOC). Points represent the causal estimate for the odds ratio (OR) derived from inverse-variance weighted MR analysis; error bars indicate 95% confidence intervals. All P-values were derived from two-sided inverse-variance weighted tests. Sample sizes for mediator–outcome analyses ranged from 41,953 to 462,117 individuals across phenotype combinations. Associations with an FDR < 0.05 were considered statistically significant after correction for multiple comparisons. Associations with the ENOC subtype that were significant after FDR correction for multiple testing are highlighted in blue.