Shared genetic architecture between metabolic dysfunction-associated steatotic liver disease and cardiometabolic traits comorbidities: a genome-wide pleiotropic and multi-omics study

Aim: While cardiometabolic disorders and metabolic dysfunction-associated steatotic liver disease (MASLD) frequently coexist, the genetic connections and causes are not clearly understood. This study aimed to explore their shared genetic architecture to elucidate the mechanisms driving their comorbidity. Methods: Using summary statistics from genome-wide association studies (GWASs) on MASLD and 29 cardiometabolic traits (CMTs), we assessed their genetic correlation and causality, and identified shared genetic loci, genes, pathways, cell types, and tissues. Additionally, shared biological mechanisms were uncovered using single-cell RNA sequencing data. Results: Significant genetic correlations were detected between MASLD and 17 CMTs, encompassing cardiometabolic diseases, glucose, lipids, adiposity, and inflammatory markers, after adjusting for multiple testing (p .adjust < 0.05). Cross-trait analysis yielded a total of 166 shared risk SNPs (including those located in or near TRIB1 , LPL , PNPLA3 , GCKR , and PPARG ). Subsequent colocalization highlighted 73 genetic loci associated with both MASLD and CMTs, with rs429358 (APOE ) consistently prioritized in HyPrColoc. Common genes were identified (such as NPC1 , MST1R , TMBIM1 , IRAK1BP1 , L3MBTL3 , RBM6 , and RGS19 ), with significant enrichment in cholesterol metabolism, glucose metabolism, immune inflammation, and long-term depression. Shared tissue-specific heritability enrichment was identified in the liver, adipose, artery, adrenal gland, and brain tissue. Moreover, shared enrichment was observed in specific cell types (epicardial adipocytes, erythroid progenitor cells, hepatocytes, glial cells, macrophages, monocytes, and myeloid cells). The expressions of APOE and LPL , which showed colocalization between MASLD and CMTs, were significantly altered in the macrophages of patients with MASLD compared to those of controls. Causality and potential medications were also explored. Conclusion: Multiple biological pathways contribute to the comorbidity between MASLD and cardiometabolic disorders, with lipid metabolism emerging as a critical factor. This study provides valuable insight into the possible mechanisms underlying their comorbidity and offers potential directions for future therapeutic innovations.