Beyond BMI: A Mendelian Randomization Study of the Causal Effects and Mediating Pathways of Regional Adipose Tissue Depots on Polycystic Ovary Syndrome.

Background: Previous studies suggest that increased body fat is associated with polycystic ovary syndrome (PCOS) risk. Recent evidence highlights that the distribution of adipose tissue may play a more critical role in predicting PCOS risk compared to total fat mass; however, causal relationships remain unclear. This Mendelian randomization (MR) study aimed to investigate the causal associations between body mass index (BMI)-independent regional adipose tissue distribution and PCOS risk.

Methods: Female-specific data on regional adipose tissue depots (n = 19,273), independent of BMI and height, including gluteofemoral adipose tissue (GFAT), abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT), and related adipose tissue ratios, were derived from large-scale genome-wide association studies. Independent genetic instruments were selected based on genome-wide significance (P < 5 × 10^-8), and the Steiger test confirmed causal direction. Causal associations were validated through meta-analysis combining discovery and replication PCOS datasets. Additionally, two-step mediation analysis was performed to investigate five potential mediators: sex hormones, lipid metabolism, glucose metabolism, adipose-specific factors, and inflammatory markers.

Results: Genetically predicted higher GFAT volume demonstrated a significant causal protective effect on PCOS risk (OR = 0.845, 95% CI: 0.735-0.971). This protective effect was predominantly mediated through reductions in fasting insulin (58.37%, 95% CI: 27.66-89.08%) and leptin (51.75%, 95% CI: 33.54-75.41%). Other mediators included the homeostasis model assessment of insulin resistance (HOMA-IR; 37.20%), sex hormone-binding globulin (SHBG; 24.74%), bioavailable testosterone (BT; 11.99%), and triglycerides (TG; 9.52%). Additionally, suggestive evidence driven by a single genetic instrument linked higher VAT/ASAT, VAT/GFAT, and ASAT/GFAT ratios to increased PCOS risk (OR > 1). Sensitivity analyses and supplementary methods confirmed the robustness of these findings.

Conclusion: This study provides causal evidence supporting the protective role of GFAT against PCOS and identifies critical metabolic and hormonal pathways as mediators. These results highlight the significance of adipose tissue distribution patterns in the pathogenesis of female endocrine disorders.