Shared genetic architecture between PMOS and MASLD: a transcriptome-wide association study prioritizes candidate hepatic genes

Polyendocrine metabolic ovarian syndrome (PMOS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are highly prevalent metabolic disorders that frequently co-occur, yet their shared genetic underpinnings remain poorly understood. We integrated genome-wide association study summary statistics to explore the genetic architecture among PMOS, testosterone (T), free androgen index (FAI), and MASLD. Liver-based transcriptome-wide association studies (TWAS) were performed to identify genes whose genetically predicted expression was associated with androgen-related traits, followed by co-localisation analysis to prioritise candidate genes sharing genetic signals with MASLD. Functional annotation and pathway enrichment analyses were conducted to characterise relevant biological processes, and a prenatal androgen (PNA)-induced mouse model was used to evaluate the candidate gene in vivo. Genetic correlation analysis revealed significant shared heritability between MASLD and androgen-related traits, while conditional Q-Q plots demonstrated non-random enrichment of MASLD-associated variants among androgen-associated loci. We also identified a novel FAI-associated locus on chromosome 5, further supporting shared genetic architecture of between androgen-related traits and MASLD. Liver-based TWAS followed by colocalisation analysis prioritised nine genes, among which integrative analyses highlighted KPNB1 as the leading candidate, supported by in vivo evidence that hepatic Kpnb1 upregulation accompanied steatosis and dyslipidaemia in PNA mice. Our findings advance understanding of the shared genetic architecture between PMOS and MASLD and prioritise KPNB1 as a biologically supported candidate linking androgen dysregulation to hepatic lipid metabolism. These results reinforce PMOS as a multisystem metabolic disorder and provide new molecular insights into the increased burden of MASLD among affected women.