Background & Aims. Metabolic-associated steatotic liver disease (MASLD) affects individuals across a range of body weights, but little is known about the genetic determinants of this condition in individuals with normal BMI. This study aimed to identify genetic variants contributing to hepatic fat levels in normal-weight individuals. Methods. We conducted 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/m^2) of European ancestry from the UK Biobank. We employed a case-control (CC) design to assess hepatic steatosis and a quantitative trait (QT) design for liver fat content. Fine mapping was conducted to identify potential causal variants, while Multi-marker Analysis of GenoMic Annotation (MAGMA) and transcriptome-wide association studies (TWAS) were performed to assess gene-level associations and impute liver-specific gene expression. Results. We identified 241 (CC-GWAS) and 418 (QT-GWAS) significant variants located predominantly in genes on chromosomes 19 and 22, including PNPLA3, TM6SF2, and SAMM50. Fine mapping revealed three potential causal variants in SUGP1, GATAD2A, and MAU2. MAGMA analysis identified eight genes in CC-GWAS and 19 in QT-GWAS, including the novel association with RFXANK. TWAS detected MBOAT7 and SAMM50, with SAMM50 being further implicated as a potential causal gene through TWAS fine mapping. Conclusions. This study, only the second to identify associations at the genome-wide level, represents a significant step forward in understanding the genetic basis of hepatic steatosis in normal-weight individuals, identifying both novel and established genetic variants. These findings provide insights into the pathophysiology of MASLD in this understudied population, emphasizing the importance of genetic predisposition beyond obesity-related mechanisms, and provide potential targets for personalized treatment and prevention strategies.

The authors have declared no competing interest.

This study was funded by the National Institutes of Health, NIDDK branch.

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This study used anonymized datasets from the UKB and access was acquired through a registration process, which qualifies as exempt from IRB approval. Therefore, the ethics committee at the Translational Genomics Research Institute waived ethical approval for this work.

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