Female-specific metabolic genetic liability reveals a separable metabolic dimension of polycystic ovary syndrome.

چکیده اصلی

BACKGROUND: Polycystic ovary syndrome (PCOS) frequently co-occurs with obesity, insulin resistance, dyslipidaemia and metabolic syndrome (MetS). However, whether this metabolic burden represents secondary comorbidity or an intrinsic component of PCOS genetic architecture remains unclear. METHODS: We used genomic structural equation modelling to construct female- and male-specific hierarchical MetS latent factors from six sex-stratified cardiometabolic GWAS, including BMI, waist circumference, triglycerides, HDL cholesterol, type 2 diabetes and fasting glucose. Sex-specific MetS genetic architecture was evaluated using latent factor GWAS, sex-difference testing, MiXeR, MAGMA and GSA-MiXeR. To assess the relationship between MetS liability and PCOS, we performed CPASSOC, conjunctional FDR, Bayesian colocalization, GWAS-by-subtraction and GenomicSEM-based mediation analysis. RESULTS: Female and male MetS factors shared a highly overlapping polygenic backbone, but their genetic correlation was significantly below unity. Among comparable lead variants, 9.1% showed sex-dimorphic effects, and MiXeR estimated an approximately fourfold larger female-specific causal component than the male-specific component. Cross-trait analysis identified 45 candidate pleiotropic loci linking PCOS with the female MetS factor, 34 conjFDR-supported shared loci and 10 loci with strong Bayesian colocalization evidence, including FTO, ERBB3, FGFR1, KLF16 and TEX41. GWAS-by-subtraction showed that 16.7% of PCOS genetic variance was shared with female MetS, whereas 83.3% remained MetS-independent and retained stronger reproductive-endocrine features. Variant-level mediation further showed that MetS-mediated effects were locus-specific rather than a global amplifier of PCOS risk. CONCLUSIONS: This study redefines the metabolic comorbidity of PCOS as a separable, female-biased genetic dimension embedded within, but distinct from, the predominant reproductive-endocrine genetic architecture of PCOS. These findings provide a genetic framework for resolving reproductive-metabolic heterogeneity in PCOS and may inform future risk stratification and precision management of metabolic complications in women with PCOS.

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