Genetic analyses identify the first two genetic loci associated with sporadic pigment dispersion syndrome and indicate myopia is a causal factor for disease onset

Abstract

Purpose : Pigment dispersion syndrome (PDS) affects 2.45% of people of European ancestry and is highly correlated with myopia. In some cases, PDS can progress to pigmentary glaucoma (PG) leading to irreversible loss of vision with a relatively young average age of onset. The purpose of this study was to identify genetic variants associated with PDS risk, providing greater understanding of its genetic aetiology, and subsequently investigate whether myopia plays an active role in PDS and PG development.

Methods : GWAS was performed by meta-analysing four cohorts with a total of 574 PDS cases, and 52,627 controls all of European ancestry. Two-sample Mendelian randomisation was utilised to determine a causal relationship between myopia and PDS; uncorrelated variants, significantly associated (p<5x10^-8) with myopia in an independent analysis were selected as instrumental variables.

Results : Variants clustered at two distinct genomic loci were associated with PDS with genome-wide significance (p<5x10^-8). Associations at these loci implicate two previously unreported genes involved in human PDS development. The strongest association was within the gamma-secretase activator protein (GSAP) (p=6.0x10^-10), which participates in the same pigmentation pathways as PDS associated genes previously identified in familial studies. Significantly associated SNPs account for 3.1% of PG risk (p=1.9x10^-7), which is 6.9% of the total PG SNP heritability (0.45). Two-sample Mendelian randomisation analyses indicated that myopia exerts direct, causal effects over PDS risk (p=8.9x10^-7) with each decrease in spherical equivalent by one dioptre translating to an odds ratio of 1.4 for PDS risk.

Conclusions : Common genetic variants account for a considerable proportion of risk for PDS and PG. This is the first study to identify specific genetic risk factors for these conditions among unrelated cases outside of familial studies and provides insight into the genetic pathways of these conditions. Though myopia is known to correlate with PDS and PG, this study provides strong evidence that this correlation is a consequence of myopia exerting causal effects over PDS.

This is a 2021 ARVO Annual Meeting abstract.