Genetic Variants Influencing Liver Fat in Normal-Weight Individuals of European Ancestry

Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs across a wide spectrum of body weights, yet the genetic determinants underlying hepatic steatosis in individuals with normal BMI remain underexplored. This study aimed to identify genetic variants associated with liver fat fraction in normal-weight individuals. We performed a genome-wide association study (GWAS) using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) data from 10,918 normal-weight participants (BMI <25 kg/m2) of European ancestry in the UK Biobank. Hepatic steatosis and liver fat content were assessed using both case-control (CC; 815 cases with MRI-PDFF ≥5% vs. 10,103 controls with MRI-PDFF <5%) and quantitative trait (QT; N = 10,918, with MRI-PDFF as a continuous outcome) designs. Fine mapping prioritized potential causal variants. Gene-level associations were evaluated using multi-marker analysis of genomic annotation (MAGMA), and liver-specific gene expression was imputed for transcriptome-wide association studies (TWAS). We identified 241 genome-wide significant variants in the CC-GWAS and 418 in the QT-GWAS, with most located on chromosomes 19 and 22, including known loci such as PNPLA3, TM6SF2, and SAMM50. Fine-mapping analyses prioritized three candidate causal variants in SUGP1, GATAD2A, and MAU2. MAGMA identified eight genes in CC-GWAS and 19 in QT-GWAS, including a novel association with RFXANK. TWAS supported the involvement of MBOAT7 and SAMM50, with fine mapping further implicating SAMM50 as a likely causal gene. This study, one of the first to detect genome-wide associations for hepatic steatosis in normal-weight individuals, identified both novel and established genetic loci. These findings highlight the role of genetic susceptibility independent of obesity-related pathways and may inform targeted strategies for MASLD prevention and treatment in this understudied population. This study provides new insights into the genetic risk factors underlying metabolic dysfunction-associated steatotic liver disease in individuals with a normal BMI, a group often under-represented in steatotic liver disease research. Leveraging large-scale genomic and imaging data from the UK Biobank, we identified both known and novel variants associated with liver fat accumulation, emphasizing that genetic predisposition can drive hepatic steatosis independently of excess adiposity. While the study is based on individuals of European ancestry, future research should assess the relevance of these findings in more diverse populations to ensure broader clinical applicability. These results may help inform future strategies for early risk stratification and targeted prevention in metabolically vulnerable, normal-weight individuals.