Cross-Tissue Transcriptome-Wide Association Study and TWAS-FOCUS Fine-Mapping Reveal Novel Susceptibility Genes for Primary Open-Angle Glaucoma.

Purpose

Primary open-angle glaucoma (POAG) is a common eye disorder that can lead to irreversible vision loss. Although genome-wide association studies (GWAS) have identified several genetic loci associated with POAG risk, the specific causative genes and mechanisms remain unclear.

Methods

This study utilized the Unified Test for Molecular Signature (UTMOST) for cross-tissue analysis, along with Functional Summary-based Imputation (FUSION) and Fine-mapping of Causal Gene Sets (FOCUS) for single-tissue validation, analyzing a POAG GWAS dataset comprising 192,702 subjects (15,229 cases and 177,473 controls) in conjunction with Genotype-Tissue Expression Project (GTEx) version 8 eQTL files. Additionally, multi-marker analysis of genomic annotation (MAGMA), Mendelian randomization, and colocalization analysis were used to further validate candidate genes.

Results

The cross-tissue transcriptome-wide association study (TWAS) analysis identified 33 significant genes associated with POAG, whereas single-tissue validation revealed 18 significant genes. Conditional and Joint (COJO) analysis consistently identified nine candidate genes, with AFAP1 showing a significant causal relationship with POAG (P < 0.05), whereas FMNL2 did not (P > 0.05). Colocalization analysis indicated strong colocalization of AFAP1 with POAG in skeletal muscle and breast tissue, and significant colocalization of FMNL2 in the terminal ileum.

Conclusions

This comprehensive analysis identified AFAP1 and FMNL2 as key susceptibility genes for POAG, highlighting FMNL2's regulatory role in aqueous humor outflow pathways. These findings provide new insights into the genetic architecture of POAG and potential targets for future research and therapeutic interventions.

Translational relevance: This study bridges basic genomics and clinical care by identifying and validating AFAP1 and FMNL2 as novel susceptibility genes for POAG, offering potential targets for early diagnosis and therapeutic intervention.