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[Preprint]. 2025 Jun 20:2025.06.18.25329836.
doi: 10.1101/2025.06.18.25329836.

Genome-Wide Insights into the Genes and Pathways Shaping Human Foveal Development

Callum Hunt  1 , Ha-Jun Yoon  1 , Alvin Lirio  1 , Kayesha Coley  2   3 , Jun Wang  4 , Nick Shrine  2 , Jianming Shao  4 , Gail DE Maconachie  1   5 , Zhanhan Tu  1 , Jonathan H Zippin  6 , Pirro G Hysi  7   8   9 , Christopher J Hammond  7   8   9 , Ala Moshiri  10 , Rui Chen  11 , Martin D Tobin  2   3 , Chiara Batini  2   3 , Mervyn G Thomas  1   12   13   3
Affiliations

Genome-Wide Insights into the Genes and Pathways Shaping Human Foveal Development

Callum Hunt et al. medRxiv. .

Update in

Abstract

Here we report the first genome-wide association study of foveal pit depth. In a cohort of 61,269 individuals, we identified 123 genome-wide significant loci associated with pit depth, including 47 novel associations not previously linked to macular traits. Using 12 complementary variant-to-gene mapping strategies, we prioritised 128 putative causal genes, 64 of which have not previously been implicated in foveal development. Our findings reveal previously unrecognised biological influences on foveal morphogenesis, including retinoic acid metabolism (implicating CYP26A1 for the first time in human foveal development), extracellular matrix and cytoskeletal dynamics, and retinal cell fate determination. In addition, rare-variant analysis uncovered two further gene associations, including ESYT3, a gene not previously linked to foveal structure. Together, these results provide new insights into the genetic architecture and molecular pathways underlying human foveal development, and offer a foundation for future functional studies aimed at characterising foveal development and disease.

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Conflict of interest statement

Declaration of Interests MDT reports funding from Orion Pharma outside the scope of the submitted work. MDT has research collaborations with GlaxoSmithKline unrelated to the current work.

Figures

Figure 1.
Figure 1.
Manhattan and quantile-quantile (QQ) plots for genome-wide association analysis of foveal pit depth. The Manhattan plot displays genome-wide association results, with each point representing a genetic variant. The x-axis indicates chromosomal position, and the yaxis shows the −log (p-value). The red dotted lines represent the genome-wide significance threshold (P < 5× 108). The QQ plot compares observed versus expected −log (p-values) under the null hypothesis, with the genomic inflation factor (λGC) provided as a measure of population stratification or confounding.
Figure 2:
Figure 2:
Summary of the variant-to-gene evidence supporting putative causal genes. Evidence for novel gene associations with foveal pit depth is highlighted in blue, while genes previously reported in GWAS of the macular region or associated with known foveal diseases are shaded in grey. Columns are ordered by the number of genes implicated by each line of evidence.
Figure 3:
Figure 3:
Schematic representation of the retina and foveal region within the human eye. Putative causal genes relevant to prioritised functional groups involved in foveal development are displayed alongside their respective functional categories. Genes highlighted in bold are novel gene associations not reported in previous GWAS of the macular region or as foveal disease genes.
Figure 4:
Figure 4:
Abnormal foveal morphology in participants heterozygous for rare-variant associations. (A) Average retinal thickness maps across the macula, measured from the internal limiting membrane (ILM) to Bruch’s membrane (BM). Maps are shown for the 1KGP-EUR-like foveal pit depth cohort and for individuals heterozygous for 11:66560171-T (ACTN3) or 3:138472579-A (ESYT3). (B) Comparison of foveal pit depth between the 1KGP-EUR-like foveal pit depth cohort and participants heterozygous for 11:66560171-T (ACTN3) or 3:138472579-A (ESYT3).
See this image and copyright information in PMC

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