Leveraging drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans

Zhong, Yi; De, Tanima; Mishra, Mrinal; Avitia, Juan; Alarcón, Cristina; Perera, Minoli

doi:10.1016/j.ajhg.2022.12.005

The American Journal of Human Genetics

2023

DOI: 10.1016/j.ajhg.2022.12.005

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Leveraging drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans

Yi Zhong¹,

Tanima De²,

Mrinal Mishra³

et al.

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2024

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Identification of genes conferring individual-level variation responsible for metabolic dysfunction-associated steatohepatitis using single-cell eQTL analysis

Hong,

Mun,

Lee

et al. 2024

Preprint

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its medical and socioeconomic impacts, driven by diverse genetic and environmental factors. To address the urgent need for individually tailored therapies, we performed single-cell expression quantitative trait loci (sc-eQTL) analysis on liver biopsies from 25 MASLD patients and 23 controls. This approach identified over 3,500 sc-eQTLs across major liver cell types and cell state-interacting eQTLs (ieQTLs) with significant enrichment for disease heritability (for MASLD trait, ieQTL enrichment odds ratio = 10.27). We integrated transcription factors (TFs) as upstream regulators of ieQTLs, revealing 601 functional units (quartets) composed of TFs, cell states, ieSNPs, and ieGenes. From these results, we pinpoint the loss of an eQTL in EFHD1 during hepatocyte maladaptation associated with genotype-specific regulation by FOXO1, further contributing to the risk of MASLD. Our approach underscores the role of eQTL analysis in capturing crucial genetic variations that influence gene expression and clinical outcomes in complex diseases.

show abstract

Identification of genes conferring individual-level variation responsible for metabolic dysfunction-associated steatohepatitis using single-cell eQTL analysis

Hong,

Mun,

Lee

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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Leveraging drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans

Cited by 1 publication

References 57 publications

Identification of genes conferring individual-level variation responsible for metabolic dysfunction-associated steatohepatitis using single-cell eQTL analysis

Identification of genes conferring individual-level variation responsible for metabolic dysfunction-associated steatohepatitis using single-cell eQTL analysis

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