Genome-wide insights into the shared genetic landscape between metabolic dysfunction-associated fatty liver disease and cardiovascular diseases

Background& Aims Multiple epidemiological studies have suggested an association between Metabolic dysfunction-associated fatty liver disease (MAFLD) and cardiovascular diseases (CVDs). However, the genetic components that are shared between the two remain unclear. Methods This genome-wide pleiotropic association study integrated comprehensive genome-wide association studies (GWAS) summary data from publicly available sources within European populations. It employed a range of genetic approaches to analyze the shared genetic architectures between MAFLD and six CVDs: atrial fibrillation (AF), coronary artery disease (CAD), venous thromboembolism (VTE), heart failure (HF), peripheral artery disease (PAD), and stroke. Initially, we examined the genetic correlation and overlap between these conditions. Subsequently, Mendelian Randomization (MR) analysis was conducted to investigate potential causal relationships. Finally, we explored horizontal pleiotropy at the levels of single nucleotide polymorphisms (SNPs), genes, and biological pathways to further elucidate the shared genetic mechanisms underlying. Results We observed significant genetic associations between MAFLD and four CVDs, including CAD, HF, PAD, and VTE. However, we noted extensive genetic overlap in all but MAFLD-AF. MR analysis established causal relationships from MAFLD to both AF and PAD. Regarding horizontal pleiotropy, 49 pleiotropic loci were identified at the SNP level with functional annotations, 13 demonstrating strong evidence of colocalization. At the gene level, 14 unique pleiotropic genes were found, with SAMM50 (located at 22q13.31) being particularly notable. Further pathway enrichment analysis indicated that these genes significantly contribute to the pathway of establishment of protein localization to membrane, highlighting their pivotal role in the pathophysiology of both MAFLD and CVD. Conclusions In all, our research proved the shared genetic architectures and mechanisms between MAFLD and CVD and elucidated their shared genetic etiology and biological mechanisms. Impact and implications Metabolic dysfunction-associated fatty liver disease (MAFLD) has reached a prevalence of 25-30% worldwide and has emerged as a global leading cause of liver-related morbidity and mortality. Studies have shown that people with MAFLD have a higher risk of cardiovascular disease (CVD) than the general population and there is currently no effective drug to treat the comorbidity of the two, which imposes a burden on the socioeconomic situation and the adverse effects are still rising. Therefore, it is critical to understand how MAFLD affects CVD. Our study provides unique insights into the mechanisms of comorbidity between MAFLD and CVD. The increasing number of complications has prompted us to explore new treatment options, so our study has important clinical significance. Graphical abstract Highlights The first comprehensive and systematic study to explore the common genetic components between MAFLD and CVD. MAFLD and CVDs share genetic architectures and mechanisms. Genetically predicted MAFLD increases the risk of AF and PAD. The effects of SAMM50 (located at 22q13.31) on lipid metabolism support the comorbidity of MAFLD and CVDs. The localization of lipid droplet related contact site proteins to the membrane plays a key role in the comorbidity of MAFLD and CVD.