Identification of circadian rhythm-associated genes and therapeutic targets in myopia with dynamics simulation: a multiomics study using machine learning algorithms and Mendelian randomization

📖 Top 50% JournalJan 6, 2026Journal of computer-aided molecular design

Genes linked to daily body clock rhythms and possible treatments for nearsightedness identified using computer analysis

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Four circadian rhythm-related key genes associated with myopia were identified, including UTS2, BTBD9, S100A3, and LGALS9.

A small molecule, 8-Bromo-cAMP, showed the highest binding efficiency to BTBD9 and UTS2, with a binding energy of -37.5 kcal/mol for the complex.
Mendelian randomization analysis indicated a significant association between UTS2 and myopia, with a P value of 0.013.
The dynamics simulation analysis confirmed the stability of the UTS2-BTBD9 complex binding with 8-Bromo-cAMP.
Differential expression analysis highlighted circadian-related genes linked to refractive errors, though mechanisms remain unclear.
Comprehensive immune infiltration analysis was performed in relation to the identified key genes.

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The prevalence of myopia is rising, with genetic and environmental factors playing key roles. Disruptions in circadian melatonin rhythms are also linked to refractive errors, though exact mechanisms remain unclear. Differential expression analysis on the GSE136701 dataset identified circadian-related genes. GSEA, GO, and KEGG analyses revealed key genes. To identify key genes, seven machine learning models were employed, and their performance was evaluated using ROC curve analysis. The correlation genes were further assessed. Concurrently, we performed a comprehensive analysis of immune infiltration and correlation pertaining to these pivotal genes. Additionally, potential target drugs were screened using the DSigDB database, and both protein-protein and molecular docking analyses were performed. To investigate the causal relationship between target genes and myopia, two-sample MR analysis was conducted. Finally, single-cell annotation and cell-cell communication analyses were carried out on the GSE235684 dataset. We preliminarily identified four circadian rhythm-related key genes: UTS2, BTBD9, S100A3, and LGALS9. We identified 8-Bromo-cAMP as the small molecule exhibiting the highest binding efficiency to BTBD9 and UTS2, with a docking binding energy of - 37.5 kcal/mol for the BTBD9-UTS2 complex and - 6.8 kcal/mol for the complex-small molecule interaction. The dynamics simulation analysis has further corroborated the dynamic stability of the UTS2-BTBD9 complex binding with 8-bromo-cAMP. Toxicological profiling of the selected small molecule 8-Bromo-cAMP was conducted using Protox-3.0 and ADMEtlab3.0. Additionally, Mendelian randomization analysis revealed a significant association between UTS2 and myopia, with an inverse variance weighted (IVW) P value of 0.013 (OR 0.532, 95% CI 0.323-0.877). Cochran's Q test revealed no significant heterogeneity in either MR-Egger (Q = 3.753, P = 0.289) or IVW (Q = 3.893, P = 0.421) estimates, supporting the use of fixed-effects models.

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