Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Genes Associated With POAG

Area of Science:

• Genetics
• Ophthalmology
• Genomics

Background:

• Genome-wide association studies (GWAS) have identified multiple genetic loci linked to primary open-angle glaucoma (POAG).
• Functional understanding of these loci is hindered by challenges in noncoding regions and complex linkage disequilibrium.
• Integrating genomic and transcriptomic data is crucial for identifying systemic regulatory genes in POAG pathogenesis.

Purpose of the Study:

• To bridge the gap in functional insights for POAG by integrating genomic and multitissue transcriptomic data.
• To identify novel systemic regulatory genes associated with POAG.
• To elucidate the genetic architecture and regulatory mechanisms underlying POAG.

Main Methods:

• Cross-tissue transcriptome-wide association studies (TWAS) were performed using POAG genomic data (FinnGen) and expression quantitative trait loci (eQTL) data (GTEx v8).
• The Unified Test for Molecular Signature, Functional Summary-based Imputation, and Multi-marker Analysis of Genomic Annotation were employed for cross-tissue and tissue-specific association analyses.
• Summary data-based Mendelian randomization and colocalization analyses were conducted to assess functional implications of candidate genes.

Main Results:

• Six candidate genes (AFAP1, CALCRL, KREMEN1, MTMR3, GFPT1, TRIOBP) were identified through integrated evidence.
• Three novel genes (CALCRL, MTMR3, GFPT1) were found to be associated with POAG.
• Mendelian randomization confirmed protective effects for AFAP1, CALCRL, KREMEN1, and MTMR3, and a risk role for GFPT1 in POAG.

Conclusions:

• This study successfully identified six genes, including three novel ones, associated with POAG.
• The findings provide novel insights into the genetic architecture of POAG.
• The research highlights the importance of systemic regulatory genes in POAG pathogenesis.