Photoreceptor thinning linked to genetic AMD susceptibility in Asians

Thinner photoreceptor layers in the central macula appear indicative of genetic predisposition to age-related macular degeneration (AMD) in healthy Asians, as shown in a study from Singapore.

The association of photoreceptor thinning with overall genetic susceptibility to AMD extends to the combined effects of the biological pathways that play a role in AMD development, namely complement cascade and lipoprotein metabolism pathway, and is most pronounced at the L7 and L9 layers of the retina, according to the investigators.

“These structural changes occur at the macula even before AMD onset, suggesting that the photoreceptor layer thickness can serve as an early biomarker for AMD, and topographic variation should be considered,” they said.

For the study, the investigators looked at 1,579 healthy individuals (782 Chinese, 353 Malays, and 444 Indians) who participated in the multiethnic Singapore Epidemiology of Eye Diseases study. The mean age of the cohort was 53.1 years, and 49.2 percent of the participants were female.

The participants underwent spectral-domain optical coherence tomography (OCT) and automatic segmentation of individual retinal layers to generate 10 retinal layer thickness measurements at each ETDRS* subfield. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRS_AMD).

Genetic risk for AMD was assessed using SNPs and summarized into two PRS_AMD, with one based on the entire genome and the other on specific biological pathways related to AMD. Three SNPs emerged as most strongly linked to retinal thinning at the central subfield, namely CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085.

The overall PRS_AMD was significantly associated with reduced L9 layer (outer photoreceptor segment/retinal pigment epithelium complex) thickness at the central subfield. On the other hand, pathway-specific PRS_AMD for the complement cascade and lipoprotein metabolism (β, −0.05 μm; p=0.0061) were associated with thinner L9 and L7 (inner and outer photoreceptor segments, respectively) layers at the central subfield. [Ophthalmol Sci 2023;3:100396]

“Indians demonstrated the thinnest retinal thickness for the same genotype and for the overall PRS_AMD compared with the Chinese, particularly in the central subfield, suggesting a greater genetic susceptibility to AMD,” the investigators noted.

“This is an interesting finding. As the PRS_AMD in our study is based on East Asians (mainly Chinese populations), the strong association for photoreceptor layers in the Indians suggests that the transethnic PRS_AMD can be applied to other populations. This is also consistent with our previous findings that Indians have the thinnest central subfield and overall macular thicknesses compared with the Chinese and Malays,” they added. [Br J Ophthalmol 2019;103:894-899]

The overall findings are in line with those of the UK Biobank studies and support research that has implicated complement factor and lipoprotein metabolism pathway dysfunction in the development of AMD. [Sci Rep 2021;11:23255; Ophthalmology 2022;129:694-707; Biomedicines 2021;9:763; Prog Retin Eye Res 2018;67:56-86]

*Early Treatment Diabetic Retinopathy Study