Mendelian Randomization Analyses Reveal Causal Relationships between Brain Structural Connectivity and Risk of Polycystic Ovary Syndrome.

Objectives: To explore the relationship between brain structural connectivity and polycystic ovary syndrome (PCOS).

Design: Two-sample Mendelian randomization (2SMR) was conducted by querying a relevant European population genome-wide association studies (GWAS) database about the anatomical connections of the brain and polycystic ovarian syndrome from the Ieu Open GWAS Project database. Two hundred six brain structural connectivity-related single-nucleotide polymorphisms (SNPs) were evaluated as instrumental variables (IVs).

Methods: To investigate the potential causal effect between brain structure and PCOS, we applied several statistical models, including inverse variance weighting (IVW), weighted median (WME), MR-Egger regression, simple mode, and weighted mode approaches.

Results: IVW analysis indicated significant associations between certain white matter tracts and PCOS risk, including the connection between the right default mode network and the amygdala (OR = 1.559; 95% CI = 1.028-2.36; p = 0.037), as well as the pathway linking the right somatomotor and limbic networks (OR = 1.800; 95% CI = 1.077-3.009; p = 0.025). Additionally, negative correlations with PCOS risk were observed in white matter tracts involving limbic-control and limbic-thalamic connections across both hemispheres, as well as in the left somatomotor-control circuit. Horizontal pleiotropy was not detected by heterogeneity tests or sensitivity analyses that used the leave-one-out approach.

Limitations: More research involving bigger and more heterogeneous cohorts is necessary to evaluate the functional consequences of anatomical brain changes in PCOS.

Conclusion: The structural integrity of white matter tracts linking the right default mode network to the amygdala and connecting the right somatomotor and limbic networks appears to be causally associated with the development of PCOS.