Abstract
Purpose :
Glaucoma is the leading causes of irreversible blindness worldwide. Previous genome-wide association studies have uncovered over 100 loci for primary open-angle glaucoma (POAG), the most common form of glaucoma. Most of these genetic loci were identified using common variants, but the role of rare variants in POAG is largely unknown. In this study, we conducted a large-scale exome-wide association study (ExWAS) on glaucoma.
Methods :
With large amounts of data available from the UK Biobank, a cohort of half a million individuals from the United Kingdom, we analyzed exome sequencing data from 453,023 participants (15,606 cases and 437,417 controls). Using REGENIE and SAIGE, we conducted both single variants analyses and gene-based analyses for rare variants with minor allele frequency less than 0.01. Our covariates for the analyses were age, sex, and the first 10 principal components of genetic ancestry. For replication of results, we utilized the FinnGen dataset, a biobank of over 200,000 Finns.
Results :
We replicated existing rare-variant associations with glaucoma such as rs28939688 (p.Glu50Lys) in OPTN (P = 3.21 × 10-8) and rs74315329 (p.Gln368Stop) in MYOC (P = 1.01 × 10-37). Furthermore, we identified several novel genes, including MLH3 (P = 1.37 × 10-8), PRR22 (P = 1.84 × 10-8), PTBP1 (P = 2.87 × 10-8), and MIR4745 (P = 2.88 × 10-8), associated with glaucoma through gene-based analyses. These genes also showed significant associations with glaucoma phenotypes in the FinnGen cohort.
Conclusions :
These findings highlight the importance of including rare variants for gene discovery and disease associations and how they improve our understanding of the genetic architecture of glaucoma.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.