Genome-wide analyses identify 60 loci associated with liver triglyceride content

We performed a large-scale genome-wide association study meta-analysis of magnetic resonance imaging-derived liver triglyceride content across 71,488 European-ancestry participants from the UK Biobank, approximately doubling the sample size of previous genome-wide association studies 1 . We identified 60 independent loci, including 31 not previously reported, and estimated the single nucleotide polymorphism-based heritability of liver triglyceride content at 25%. Integrative fine-mapping and gene-prioritization analyses nominated candidate effector genes for 48 loci. Of the 31 newly identified variants, 14 were validated in meta-analyses of clinically diagnosed metabolic dysfunction-associated steatotic liver disease (42,163 cases and 1,646,254 controls). People in the highest versus lowest decile of a polygenic risk score for liver triglyceride content had 2.71-fold higher odds of cirrhosis and 7.47-fold higher odds of hepatocellular carcinoma. Plasma proteins associated with the liver triglyceride polygenic risk score were enriched for metabolic remodeling and inflammatory pathways, with liver-enriched protein signatures increasing and visceral adipose signatures decreasing with higher genetic risk. Together, these findings refine the genetic architecture of liver triglyceride content, linking polygenic susceptibility to downstream metabolic and inflammatory pathways and providing insights into the genetic basis of steatotic liver disease.