GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342568/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342568GEOGSEfalseGenetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Risk in Mexican Americans.Hispanics of Mexican American descent in South Texas show a very high prevalence of MASLD, with some studies reporting rates as high as 50% in adults. However, assessment of genetic risk factors underlying this prevalence is complicated by a high co-occurrence of other metabolic disorders and variable endogenous and exogenous environmental risk factors. To map the genetic architecture of MASLD hepatic steatosis risk, we conducted an epidemiological-scale investigation using human induced pluripotent stem cell (iPSC)-derived hepatocyte cultures from 193 participants in our longitudinal South Texas Family Study (STFS). iPSC-based models offer greater power to map genetic risk factors by experimentally controlling for confounding organismal and environmental factors. We combined transcriptome-wide gene expression analysis with high-content cellular measurements of neutral lipids to define a core hepatic steatosis MASLD phenotype at baseline (vehicle-treated) and following a lipid challenge. The additive genetic heritability of hepatic steatosis measures was 0.44 (p-value = 0.03) at baseline and 0.42 (p-value = 0.03) at post-lipid-challenge. Multivariable linear regression comparing each gene’s expression against hepatic steatosis measures identified 1,070 genes at baseline and 1,229 genes post-lipid challenge, whose expression showed a transcriptome-wide statistically significant association (standardized |β| ≥ 0.24; Bonferroni-corrected p-value ≤ 0.001) with baseline and post-lipid challenge hepatic steatosis measures, respectively. Functional annotation and pathway enrichment analyses of these genes implicated a broad range of hepatocellular functions, mapping an overall genetic architecture of MASLD-associated steatosis risk in Mexican Americans. The genes whose expression was positively correlated with hepatic steatosis measures suggest a direct role of variation in fatty acid (FA) and cholesterol uptake, de novo lipogenesis (DNL), and carbohydrate shunts in hepatic steatosis risk, as well as a cellular stress-associated and high-turnover metabolic state marked by elevated FA-oxidation and ketogenesis. In contrast, the genes whose expression was inversely correlated with hepatic steatosis measures suggest a significant role of the cellular cytoskeleton, hepatocyte epithelial integrity, and endosomal and autophagic clearance machinery in steatosis risk.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 sapiens[42738886]