ObjectiveTo explore the causal relationship between alterations in brain resting-state functional networks and polycystic ovary syndrome (PCOS) through two-sample Mendelian randomization (MR) analysis.MethodsThis study utilized the Genome-Wide Association Study (GWAS) database to obtain instrumental variables related to brain functional networks (exposure) from the UK Biobank (UKB), with PCOS as the outcome variable from the FinnGen database. All participants were of European ancestry. Genetic instruments were selected based on genomewide significance, linkage disequilibrium, and strength. When the number of instrumental variables was one, Wald Ratio analysis was used; otherwise, inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM) methods were employed for MR analysis to assess causality. Cochran's Q test, MR-PRESSO, and MR-Egger intercept analysis were conducted to evaluate heterogeneity and pleiotropy.ResultsThe Wald Ratio analysis revealed that at the level of paired functional connectivity, the central executive network and default mode or the central executive network located between the frontal and temporal lobes were positively correlated with the risk of PCOS (Wald Ratio OR=6.77, 95%CI: 1.34-34.36, P=0.021). Conversely, increased activation of the attention or central executive or salience mode network and the motor network located between the parietal and postcentral or precentral regions were negatively correlated with the risk of PCOS (Wald Ratio OR=0.19, 95% CI: 0.04-0.98, P=0.048). The heightened activation of the visual network and the central executive network, located between the cuneus or occipital and frontal lobes, were positively correlated with the risk of PCOS (Wald Ratio OR=3.73, 95% CI: 1.01-13.82, P=0.049). The IVW analysis showed that among the amplitude characteristic traits, the increased activation of limbic network (node) located in the frontal lobe was positively correlated with the risk of PCOS (IVW OR=2.22, 95% CI: 1.0-4.71, P=0.039); the increased activation of limbic network (node) located in the temporal or orbitofrontal region was positively correlated with the risk of PCOS (IVW OR=2.39, 95% CI: 1.17-4.86, P=0.016). The results of the auxiliary analysis were consistent with the direction and range of the β values and OR values obtained by the IVW method. The results were robust, and no evidence of heterogeneity or pleiotropy was found. Reverse MR analysis showed that, using the IVW analysis method, at the level of pairwise functional connectivity, PCOS was negatively correlated with the increased activation of default mode or central executive and default mode or salience networks located in the occipital precuneus-temporal lobe or frontal lobe or supplementary motor area (IVW OR=0.96, 95% CI: 0.93-1.00, P=0.024); PCOS was negatively correlated with the increased activation of central executive or salience and central executive or salience networks located in the parietal-frontal lobe (IVW OR=0.97, 95% CI: 0.94-1.00, P=0.044).ConclusionThere is a certain causal relationship between brain resting-state functional networks and risk of PCOS. Variations in activity within specific networks may modulate susceptibility to PCOS. PCOS may also be involved in the changes of the brain's resting-state networks. The findings lend support to the central origin theory of PCOS and provide genetic evidence for this hypothesis.