Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Area of Science:

• Genetics
• Ophthalmology
• Statistical Genomics

Background:

• Genome-wide association studies (GWAS) are crucial for identifying genetic variants associated with complex diseases.
• Joint analysis of related traits can increase statistical power to detect genetic associations, especially for variants with pleiotropic effects.
• Optic nerve head (ONH) parameters are key indicators for primary open-angle glaucoma (POAG).

Purpose of the Study:

• To perform multi-trait meta-analyses of ONH-related traits implicated in POAG.
• To identify novel pleiotropic genetic variants influencing ONH parameters.
• To validate identified variants in independent cohorts.

Main Methods:

• Applied new meta-analyses to ONH traits (cup area, disc area, vertical cup-disc ratio) and intraocular pressure.
• Utilized Haplotype Reference Consortium (HRC) imputations for genome-wide association analyses.
• Performed multi-trait analysis and replication in independent Asian cohorts imputed to 1000 Genomes.

Main Results:

• Identified two novel genome-wide significant variants: rs11158547 (in PPP1R36-PLEKHG3) and rs1028727 (near SERPINE3).
• These variants were successfully replicated in independent Asian cohorts.
• Multi-trait analysis proved effective in uncovering pleiotropic variants for ONH traits.

Conclusions:

• Multi-trait analysis is a powerful strategy for discovering novel pleiotropic variants influencing optic nerve head traits.
• The identified variants, rs11158547 and rs1028727, represent significant findings for understanding the genetic architecture of ONH parameters.
• Further validation in diverse POAG cohorts is needed due to observed heterogeneity.