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

Abstract

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.