Abstract
Purpose :
The vertical cup-disc ratio (VCDR) is a measure used in clinical evaluations to assess and track damage to the optic nerve caused by glaucoma, the leading cause of irreversible blindness worldwide. Previous genome-wide association studies have established the contribution of common genetic variants to VCDR, but the role of rare variants in VCDR remains to be uncovered. In this study, we present the largest exome-wide association study (ExWAS) on VCDR to date.
Methods :
Using data from the UK Biobank, a cohort of 500,000 individuals, we analyzed 71,317 individuals who had both whole-exome sequencing data and fundus photographs. We used convolutional neural network models to derive VCDR from the fundus images. We conducted single-variant and gene-based analyses to identify rare variants with a minor allele frequency of less than 1% and their corresponding genes associated with VCDR, using REGENIE and SAIGE and adjusting for factors such as age, sex, vertical disc diameter, and genetic ancestry.
Results :
Our results revealed several genes containing rare variants that are significantly associated with VCDR, including AMOTL1 (P = 2.86 × 10-10), SRBD1 (P = 5.29 × 10-11), CCAR2 (P = 1.71 × 10-9), and COL28A1 (P = 2.83 × 10-7). Notably, SRBD1 is associated with glaucoma and COL28A1 is a drug target for the treatment of eye disease in clinical trials.
Conclusions :
These findings demonstrate the contribution of rare variants in improving our understanding of the biological mechanisms regulating VCDR and glaucoma.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.