Objective Using genome-wide association study (GWAS) data, to systematically delineate the shared genetic architecture between metabolic dysfunction-associated steatotic liver disease (MASLD) and bipolar disorder (BP), identify pleiotropic genes, and explore the causal relationship between the two.

Methods We integrated GWAS summary data for MASLD (cases n = 4,761, controls n = 373,227) and BP (cases n = 8,946, controls n = 434,831). Linkage disequilibrium score regression (LDSC) was employed to assess genetic correlation, and cross-phenotype association analysis (CPASSOC) was used to identify shared risk loci. To enhance statistical power and pinpoint pleiotropic genes, we applied multi-trait analysis of GWAS (MTAG) and combined five gene-mapping strategies (MAGMA, GCTA-fastBAT, sCCA, CONTENT, and PWAS) to identify pleiotropic genes. Finally, we conducted bidirectional Mendelian randomization (MR) analysis to test causal relationships between the two disorders, and performed functional enrichment and tissue/cell-type specificity analyses for the shared genes identified.

Results The LDSC analysis revealed a significant positive genetic correlation between MASLD and BP (r_g = 0.356, P = 5.47×10⁻⁶). CPASSOC identified 396 shared genetic loci. By integrating multi-omics analytical strategies, we ultimately identified 22 pleiotropic genes significantly associated with both diseases, including proprotein convertase subtilisin/kexin type 9 (PCSK9), signal transducer and activator of transcription 3 (STAT3), fat mass and obesity-associated gene (FTO), and sex hormone-binding globulin (SHBG). These genes were significantly enriched in key biological pathways such as the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, the PPAR signaling pathway, and extracellular matrix organization, and were highly expressed in liver, adipose tissue, arteries, and digestive system-related cell types. However, bidirectional MR analysis did not detect a direct causal relationship between MASLD and BP. In an oleic acid-induced MASLD cell model using HepG2 cells, mRNA expression levels of PCSK9, PCK1, and CUX2 were upregulated (all P ＜ 0.05).

Conclusions The clinical comorbidity of MASLD and BP may stem from a shared genetic basis. The 22 core shared genes identified in this study are involved in multiple biological processes, including hepatic lipid metabolism, neuroinflammation, apoptosis, and stress response, providing novel genetic evidence and potential therapeutic targets for understanding the comorbidity mechanisms of the two conditions.