Unravelling genetic susceptibility and causal factors in liver health using MRI quantification of inflammation, fat and iron in the liver

Liver steatosis, fibroinflammation, and iron overload, are growing global health concerns, yet the genetic architecture and causal pathways linking liver pathology to systemic disease remain incompletely understood. We analysed MRI-derived liver traits—corrected T1 (cT1), proton density fat fraction (PDFF), and liver iron—in 37,626 UK Biobank participants. Genome-wide (GWAS), transcriptome-wide (TWAS), and cis-protein Mendelian randomisation (cis-MR) analyses were used to identify genes and proteins influencing these traits. We applied two-sample MR to assess bidirectional causal relationships with metabolic and vascular traits and used Multi-Trait Analysis of GWAS (MTAG) to enhance discovery by leveraging genetic correlations. GWAS identified 18 loci for cT1, 15 for PDFF, and 5 for liver iron, including six not previously reported. TWAS, cis-MR, and proteome-wide analyses prioritised genes (e.g., FADS1, GPAM, MBOAT7, RAD51C) and proteins (e.g., RAB2B, GPN1, GSTM4) with putative mechanistic roles. Fine-mapping refined several signals (GSTM1, TMPRSS6) to single-variant credible sets. Cell-type enrichment revealed distinct tissue contributions: hepatocytes and intestinal mucosa for cT1, adipose tissue for PDFF, and gastrointestinal tissues for liver iron. MR suggested causal effects of higher liver PDFF and cT1 on obesity-related traits, and inverse genetic associations between liver iron and coronary artery disease. MTAG identified seven additional loci (three for cT1, four for PDFF) not previously reported. This integrative imaging-genetics study reveals 13 potentially novel genes and several protein candidates implicated in hepatic steatosis, inflammation, and iron homeostasis. These findings enhance understanding of liver disease biology and may help identify new targets for early detection or treatment. This large imaging-genetics study in over 37,000 people identifies genetic and protein factors linked to liver fat, fibroinflammation, and iron levels. It shows that higher liver fat and inflammation are associated with increased cardiometabolic risk, while higher liver iron appears inversely linked to risk of heart disease. These findings highlight molecular targets such as FADS1, FUT2, TMC4, RAB2B, and GPN1, which could inform future efforts to improve early detection or treatment of liver disease and its complications in people with obesity or metabolic syndrome.