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

作者：Xuan-Yu Wang, Qiong Lyu, Yangyang Zhang, Yue Su, Hongjie Zhao, Hui‐Hui Shen, Yingyu Xie · 发表于：Metabolism and Target Organ Damage · 年份：2025 · DOI：10.20517/mtod.2024.129 · 被引用次数：3 · 研究领域：Liver Disease Diagnosis and Treatment、Diet, Metabolism, and Disease、Genetic Associations and Epidemiology

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, ar...