Relationship between genetic susceptibility to age-related macular degeneration and retinal thickness in multi-ethnic Asian populations

Abstract

Purpose : Optical coherence tomography (OCT) imaging is widely used for age-related macular degeneration (AMD) diagnosis, but whether OCT retinal thickness measurements can serve as a prodromal AMD risk marker is not well understood. We aimed to identify the individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility variants and polygenic risk score (PRS_AMD).

Methods : This genetic association study utilised data from the Singapore Epidemiology of Eye Diseases Study (population-based cohort studies of Chinese, Malays, and Indians). A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) with both retinal thickness and genotype data were included. Spectral-domain OCT and automatic segmentation of all 10 retinal layers were performed to produce individual retinal layer thickness measurements. Associations of single nucleotide polymorphisms (SNPs), and overall and pathway-specific PRS_AMD with individual retinal layer thickness measurements at each Early Treatment of Diabetic Retinopathy Study grid subfield at the macula were assessed.

Results : The overall PRS_AMD was most associated with decreased photoreceptor layer thickness [Layer (L) 9] at the central subfield (β=-0.63μm, p=5.45x10^-9). Pathway-specific PRS_AMD for the complement cascade (β=-0.53μm, p=9.42x10^-7) and lipoprotein metabolism (β=-0.05μm, p=0.0061) were associated with thinner photoreceptor layers (L9 and L7, respectively) at the central subfield. The mean PRS_AMD score was larger in the Indian population compared with the Chinese and was associated with the greatest decrease of retinal thickness at L9 (β=-1.00μm, p=2.91x10^-7; R²=5.5%). CFH, ARMS2-HTRA1, and LIPC were significantly associated with thinner photoreceptor layers. These associations with thinner photoreceptor layers were most pronounced at the central macula. At the inner and outer rings and other retinal layers, the associations were more heterogenous, i.e., associations with both thinner and thicker retina.

Conclusions : AMD genetic susceptibility manifests in photoreceptor layer thinning in healthy individuals and has a characteristic topographic variation. Structural changes occur at the macula before the onset of symptoms or signs in AMD, implying that the photoreceptor layer thickness has a potential role to be a prodromal AMD risk marker.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.