Genetic Variants and Molecular Components Associated with Metabolic Dysfunctional-Associated Steatotic Liver Disease and Depression: Shared Association of ADAMTS7 and THRAP3

Authors

• Eron G. Manusov, The University of Texas Rio Grande ValleyFollow
• Vincent P. Diego, The University of Texas Rio Grande ValleyFollow
• Marcio A. Almeida, The University of Texas Rio Grande ValleyFollow
• Jacob A. Galan, The University of Texas Rio Grande ValleyFollow
• Kathryn Herklotz, The University of Texas Rio Grande Valley
• Edwardo Abrego II, The University of Texas Rio Grande ValleyFollow
• Habiba Sultana, The University of Texas Rio Grande ValleyFollow
• Luis A. Peña Marquez, The University of Texas Rio Grande ValleyFollow
• Marco Arriaga, The University of Texas Rio Grande ValleyFollow
• Marcelo Leandro, The University of Texas Rio Grande ValleyFollow
• Juan M. Peralta, The University of Texas Rio Grande ValleyFollow
• Ana C. Leandro, The University of Texas Rio Grande ValleyFollow
• Tom Howard, The University of Texas Rio Grande ValleyFollow
• Joanne Curran, The University of Texas Rio Grande ValleyFollow
• Sandra Laston, The University of Texas Rio Grande ValleyFollow
• John Blangero, The University of Texas Rio Grande ValleyFollow
• Sarah Williams-Blangero, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

3-18-2026

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and depression frequently occur together. Identifying the genes that influence both MASLD and depression may facilitate the discovery of biological pathways associated with disease risk.

Methods: We recruited 525 participants from Mexican American families living in the Rio Grande Valley of south Texas. We collected clinical data, biometric measurements, hepatic health assessments using Vibration-Controlled Transient Elastography (VCTE), and depression evaluations determined with the Beck Depression Inventory-II. We estimated the heritability (h2) of MASLD-related measures, depression status, aspartate aminotransferase (AST), alanine aminotransferase (ALT), the AST/ALT ratio, and Vibration-Controlled Transient Elastography measurements. For each gene, we derived a genetic endophenotype representing its expression level. We then performed functional network and gene ontology enrichment analyses to characterize the underlying protein pathways.

Results: We observed significant associations between the expression of two genes, Thyroid Hormone Receptor-Associated Protein 3 (THRAP3) (h2 = 0.56 [0.45, 0.67]) and ADAM Metallopeptidase with Thrombospondin Type 1 Motif 7 (ADAMTS7) (h2 = 0.66 [0.55, 0.77]), with depression and multiple MASLD-related phenotypes. We identified 351 genes with expression levels significantly correlated with one or more MASLD phenotypes and depression. Among these, five genes—ADAMTS7, THRAP3, CHPM4A, RAB9A, and PDIA3—were jointly associated with three phenotypes: AST/ALT, ALT, and Controlled Attenuation Parameter (CAP kPa). Based on the Fisher Combined Test, only THRAP3 (p = 3.0 × 10−2) and ADAMTS7 (p = 2 × 10−2) were jointly significant for depression (BDI-II) and AST, ALT, AST/ALT ratio, FAST, and CAP (kPa). We present a protein–protein interaction network comprising nodes (proteins) and edges (interactions), and a gene ontology enrichment analysis of cellular components.

Discussion: Our findings highlight pleiotropic genes underlying MASLD and depression. Two genes, ADAMTS7 and THRAP3, warrant further investigation as potential targets for therapeutic interventions to manage MASLD and depression among Mexican Americans. These results may improve our understanding of the pathways involved in these two diseases, advance current research, and contribute to improvements in personalized medicine.

Conclusion: We identified possible shared gene expression phenotypes linking MASLD and depression, which may provide insight into a common molecular underpinning. Pathway enrichment and gene analysis were used to help refine networks and enhance our understanding of complex gene-environmental interactions and their implications for precision medicine.

Comments

© 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.    

Recommended Citation

Manusov, E. G., Diego, V. P., Almeida, M., Galan, J. A., Herklotz, K., Abrego, E., ... & Williams-Blangero, S. (2026). Genetic Variants and Molecular Components Associated with Metabolic Dysfunctional-Associated Steatotic Liver Disease and Depression: Shared Association of ADAMTS7 and THRAP3. Genes, 17(3), 343. https://doi.org/10.3390/genes17030343

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Genes

DOI

10.3390/genes17030343