ORIGINAL RESEARCH article
Front. Med.
Sec. Hepatobiliary Diseases
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1623367
This article is part of the Research TopicDigital Technologies in Hepatology: Diagnosis, Treatment, and Epidemiological InsightsView all 12 articles
Genetic Insights into Alcohol-Associated Liver Disease: Integrative Transcriptome-Wide Analysis Identifies Novel Susceptibility Genes
Provisionally accepted
- 1Shandong First Medical Univercity, jinan, China
- 2Shandong Provincial Hospital Affiliated to Shandong First Medical University, jinan, China
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Alcohol-associated liver disease (ALD) is a chronic condition influenced by both genetic and environmental factors. While GWAS has identified ALD-related loci (PNPLA3, MBOAT7, TM6SF2), underlying genetic mechanisms and therapeutic targets remain unclear.This study utilized the FinnGen R12 dataset (488,982 participants) and GTEx v8 eQTL data to perform a cross-tissue transcriptome-wide association study (TWAS) using UTMOST, with single-tissue validation via FUSION. Gene-level association analysis (MAGMA), Mendelian randomization (MR), and colocalization were applied to evaluate causal links. Functional significance was assessed through GeneMANIA, drug enrichment, and molecular docking analyses.Three ALD susceptibility genes-AFF1, C4orf36, and HSD17B13-were identified and validated. HSD17B13 may reduce ALD risk via lipid metabolism and redox balance, while AFF1 is implicated in transcription regulation. C4orf36 requires further study. Drug enrichment analysis highlighted AFF1 as a target for beta-D-allopyranose, dexbrompheniramine, and (+)-chelidonine, with molecular docking confirming strong 2 binding potential.This study identifies AFF1, C4orf36, and HSD17B13 as ALD susceptibility genes, proposing AFF1 as a potential therapeutic target, paving the way for precision medicine in ALD, though further experimental validation is needed to establish their functional relevance.
Keywords: Alcohol-related liver disease (ALD), drug enrichment analysis, genome-wide association study (GWAS), Transcriptome-wide association study (TWAS), Multi-Marker Analysis of Genomic Annotation analysis, Mendelian Randomization (MR)
Received: 05 May 2025; Accepted: 07 Jul 2025.
Copyright: © 2025 Wang, Hu, Wang, Wang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Fangfeng Liu, Shandong Provincial Hospital Affiliated to Shandong First Medical University, jinan, China
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