Exploration of associations between a prevalent Stargardt disease-associated variant in ABCA4 and retinal thickness in the general population

Abstract

Purpose : Pathogenic variants in ABCA4 are associated with Stargardt disease. One particular variant, c.5603A>T, p.Asn1868Ile, has previously been shown to be significantly enriched in Stargardt patients and is regarded as supportive of the diagnoses; however this variant is relatively common (6.3% allele frequency in Europeans). The purpose of this study was to determine whether this variant is associated with effects on macular thickness among the general population.

Methods : Quantitative OCT data using the Topcon 3D OCT-1000 Mk2 machine and genetic data from whole exome sequencing for the c.5603A>T variant was available for 20180 participants of European ancestry in the UK Biobank, following quality control. Of these, 101 were homozygous and 2610 were heterozygous for c.5603A>T. Linear regression analyses, adjusted for age and sex, were performed to test for association between this variant and total retinal thickness as well as three available segmented layer thicknesses (retinal nerve fibre layer, RNFL; ganglion cell-inner plexiform layer, GC-IPL; retinal pigment epithelium, RPE). Further linear regression analyses were performed with eight automated QC measures as the outcome variable to determine whether c.5603A>T is associated with abnormal or scans of low quality.

Results : No association was identified between c.5603A>T and retinal thickness (p=0.76) or with any of the three segmented layer thicknesses (RNFL p=0.16; GC-IPL p=0.82; RPE p=0.52). No association was identified between c.5603A>T and any of the eight quality control measures (all p>0.25). Participants with the c.5603A>T variant were also no more likely to be excluded during quality control, indicating an absence of pathogenic effects affecting scan quality. Finally, out of 144 homozygotes (pre-QC), only two (1.4%) have been diagnosed with degeneration of macula and posterior pole.

Conclusions : The c.5603A>T variant alone does not appear to affect total retinal thickness in the general population. The variant is likely therefore to require a distinct pathogenic trans-allele to cause retinopathy. Moreover, other cis- or trans-acting modifiers might contribute to pathogenicity of such a c.5603A>T genotype and in part might cause the enrichment seen in Stargardt patients.

This is a 2021 ARVO Annual Meeting abstract.