A cross-tissue transcriptome-wide association study identifies a novel susceptibility gene for age-related cataract and candidate compounds

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Author: LI Fang ¹ ZHOU Xinyang ²  HUANG Guoxin ^2, ³

Affiliation: 1.Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China 2.Evidence-Based Medicine Center, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China 3.School of Pharmacy, Qingdao University, Qingdao 266023, Shandong Province, China

Keywords: Age-related cataract Transcriptome-wide association study Mendelian randomization Colocalization analysis Molecular docking

DOI: 10.12173/j.issn.1005-0698.202608069

Reference: [Li F, Zhou XY, Huang GX. A cross-tissue transcriptome-wide association study identifies a novel susceptibility gene for age-related cataract and candidate compounds[J]. Chinese Journal of Pharmacoepidemiology, 2026, 35(9): 987-996.] DOI: 10.12173/j.issn.1005-0698.202608069.[Article in Chinese]  Copied

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Abstract

Objective To explore susceptibility genes for age-related cataract and screen candidate compounds.

Methods Genome-wide association study data on age-related cataract from FinnGen R7 were integrated with multi-tissue expression quantitative trait locus data from GTEx V8. Cross-tissue transcriptome-wide association study, single-tissue transcriptome-wide association study, conditional and joint analysis, and gene-level analysis were used to screen candidate genes, which were further evaluated using Mendelian randomization and multi-tissue colocalization analysis. The optimal gene was selected as the target for virtual screening and molecular docking.

Results Cross-tissue transcriptome-wide association study, single-tissue transcriptome-wide association study combined with conditional and joint analysis, and gene-level analysis identified 38, 120, and 680 significant genes, respectively, yielding 13 overlapping genes. Mendelian randomization analysis showed that 9 of these genes might have causal associations with disease risk. Multi-tissue colocalization analysis showed marginal colocalization signals for IHH in four tissues, with PP.H4 values ranging from 0.803 to 0.835, although none reached the stringent colocalization threshold. Virtual screening and molecular docking targeting IHH yielded 71 candidate compounds. Silibinin B ranked highest overall, with a docking score of -6.60 and an MM/GBSA ΔG Bind free energy of -41.87 kcal/mol.

Conclusion This study identified 13 candidate susceptibility genes, among which IHH was supported by Mendelian randomization and marginal colocalization evidence. Virtual screening indicated that Silibinin B had a relatively high computational binding priority for IHH, suggesting its potential as a candidate compound for subsequent drug repurposing studies. However, further experimental validation is still required.

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