Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract

Area of Science:

• Genetics and Ophthalmology
• Molecular Biology
• Bioinformatics

Background:

• Cataract is a leading cause of age-related blindness globally, with significant genetic heritability.
• Previous genome-wide association studies (GWAS) identified 55 cataract-associated loci, but causal genes remain largely unknown.

Purpose of the Study:

• To prioritize and identify novel causal genes for cataract using transcriptome-wide association studies (TWAS).
• To examine the expression patterns of identified cataract-associated genes.

Main Methods:

• Performed tissue-specific and multi-tissue TWAS using FUSION software, analyzing imputed gene expression from 54 tissues.
• Utilized meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls (GERA and UK Biobank).
• Examined novel gene expression in lens tissue using the iSyTE database.

Main Results:

• Identified 99 genes with genetically predicted expression associated with cataract.
• Discovered 20 novel cataract-associated genes not previously linked to the condition.
• Found significant enrichment of cataract-associated genes in gastrointestinal tissues, indicating non-lens involvement.

Conclusions:

• Imputation-based TWAS is effective for characterizing GWAS loci and discovering novel cataract genes.
• Gene expression influencing cataract susceptibility is not confined to ocular tissues.
• Findings advance understanding of cataract etiology and potential therapeutic targets.