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[D. Medicine/Translational Research] D-1

Identification of causal genes for nonalcoholic fatty liver

disease using multi-omics based single-cell analysis

Sung Eun Hong¹, Kyung-Suk Suh², Won Kim³*, Murim Choi¹*

¹Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea, ²Surgery, Seoul National

University College of Medicine, Seoul 03080, Korea, ³Internal medicine, Seoul National University College of

Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Korea

Background and aims Nonalcoholic fatty liver disease (NAFLD) is an emerging liver disease associated with metabolic
syndrome. Lack of effective treatment drugs urges the discovery of novel therapeutic targets. This study utilizes

multi-omics-based single-cell analysis to discover biomarkers and therapeutic targets of NAFLD. Methods Liver
biopsy samples obtained from 23 control individuals and 25 NAFLD patients were subjected to single nucleus RNA-

sequencing (snRNA-seq). DNA samples obtained from the same participants were genotyped by low coverage
whole genome sequencing. snRNA-seq profiles of the NAFLD liver were analyzed using various bioinformatics tools.

Genotype and single-cell gene expression data were integrated to map single-cell expression quantitative trait loci
(sc-eQTL). Results A total of 250K cells were detected, including hepatocytes and various non-parenchymal cells.

Pseudotime analysis recovered the zonation information in hepatocytes, differentiation pattern in cholangiocytes,
and activation process in stellate cells. Differentially expressed genes revealed cell type-specific changes in NAFLD.

Multiple sc-eQTL signals in each cell type were detected. Conclusions We present transcriptomic profile of NAFLD
in a single-cell resolution. sc-eQTL analysis identified NAFLD-associated genes and their regulatory variants in
relevant cell types. The role of putative regulatory genes and variants will be subjected to functional validation.