Genome-wide Association Study of Foveal Hypoplasia

Abstract

Purpose : Foveal Hypoplasia (FH) is a macular abnormality characterised by incomplete development of the foveal region. This abnormality is most commonly observed alongside rare inherited disorders such as albinism, but the precise mechanisms behind abnormal foveal development remain unclear. Thus, we aimed to identify genetic loci associated with FH, to provide insight into the genetic architecture of normal and abnormal foveal development.

Methods : We developed a deep learning model to analyse retinal OCT scans from a subset of UK Biobank participants, classifying individuals of European descent into FH (n=4403) and control groups (n=30069). FH classification was then used to conduct a genome-wide association study (GWAS) using these 34,472 individuals, and associations were mapped to causative genes using single nuclei multi-omics data obtained from embryonic and foetal retinal tissue. Further prioritisation of candidate genes was sought by performing CRISPR-Cas9 mediated knockout of target genes in Zebrafish. Genes were prioritised based on the impact of gene knockouts on visual function in Zebrafish, assessed using the optokinetic response.

Results : Our GWAS identified 44 genetic variants independently associated with FH (P<5×10^-8), including 31 novel variants not previously linked to FH or related traits. These novel associations include variants in genes such as TYR and OCA2, known for their roles in FH in a Mendelian context, and 28 novel genes not previously associated with FH. The identified genes operate in various biological processes such as the melanin biosynthesis pathway, melanosome function, cell fate and temporal patterning. This aligns with the functional characteristics of causative FH genes.

Conclusions : In the first GWAS study of FH, we uncovered novel genetic associations critical to understanding foveal development. The identified associations offer new avenues for research, providing mechanistic insight into the genetic factors underpinning the foveal region's development and the pathogenesis of FH.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.