Genome-Wide Cross-Trait Analysis Dissects the Shared Genetic Architecture Between Type 2 Diabetes Mellitus and...

The observational studies confirmed the high prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with Type 2 diabetes mellitus (T2DM), but whether this reflects a shared genetic etiology and exists underlying causal relationships remains unknown. Here, we utilized the largest scale cross-trait analysis from genome-wide association studies (GWASs) to investigate the shared genetic architecture and found a significant genetic correlation between T2DM and MASLD. Subsequently, we identified 581 shared risk single-nucleotide polymorphisms (SNPs) and observed consistent patterns of tissue-specific heritability enrichment in embryonic stem cells, stomach, kidney, large and small intestine, and pancreas. Of the six highly shared risk SNPs (rs7203132, rs11642015, rs58542926, rs6857, rs10404726, and rs738408), we further systematically performed regional and functional analysis. Using Mendelian randomization (MR), we discovered significant evidence for a positive causal effect with no reverse causality of T2DM on MASLD and further explained what causes causality to occur. Finally, we used an orthogonal strategy to provide genetic evidence, highlighting 11 possible comorbidity targets, most of which are located on Chromosomes 19 or 22 with five on 19p13.11, such as NCAN, MAU2, GATAD2A, TM6SF2, and GMIP. Our study sheds insights into the informed biology of comorbidity and reveals their shared genetic factors and potential drug targets.