Genetic heritability and associations of Pigmentary Glaucoma

Abstract

Purpose : Pigmentary glaucoma (PG) is an important subtype of glaucoma, as it affects younger patients which considerably reduces the window of opportunity for early detection and treatment. There is considerable scope to use biomarkers for risk stratification, but little is known about PG molecular causes that would allow estimation of individual risk to developing the disease. The purpose of this study was to quantitatively estimate the role of heritable factors in PG.

Methods : A total of 227 PG cases (58.7 ± 13.3 years) and 297 glaucoma-free controls (80.3 ± 4.8 years), all of European origin, were recruited for this pilot study. They were genotyped using Illumina’s Human Omni Express Exome 8v1-2. SNP heritability was calculated using restricted maximum likelihood analysis as implemented in the software GCTA. Association of PG with loci previously known to affect eye colour was tested. Logistic regression models were used to test the association PG and allelic dosage at the loci (directly genotyped or imputed on the Haplotype Reference Consortium information), adjusting for sex, age and principal components. Similarities in genetic architecture between PG and eye colour phenotypes were evaluated using Pearson’s correlation of effect sizes.

Results : A SNP genetic heritability estimate of 0.45 was calculated for PG, assuming a population prevalence of 0.37%. The effect sizes of previous SNPs previously associated with eye colour was strongly correlated with effect sizes over PG (ρ=0.61, p=2.7 x 10^-05), suggesting shared genetic risks between these two phenotypes. These SNPs explain 2% of PG variance in our sample (p=0.007). Due to the modest power of our pilot sample, no association at a GWAS-significant level was identified for any of the SNPs, but the strongest association for any of the eye pigmentation loci was at the OCA2 locus (p=0.02). A polygenic risk score weighted on effects over eye pigmentation was marginally associated with PG (p=0.06).

Conclusions : PG has a significant genetic basis, likely higher than our estimate of SNP heritability, because of genetic variants either not captured by SNP arrays or too rare to contribute to estimates in such a modestly powered cohort. While our pilot study did not possess sufficient power to identify genome wide associations for PG, it provided suggestive evidence of a role in PG from genes involved in eye pigmentation.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.