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

Hunt, C.; Yoon, H.-J.; Lirio, A.; Coley, K.; Wang, J.; Shrine, N.; Shao, J.; Maconachie, G. D. E.; Tu, Z.; Zippin, J. H.; Hysi, P. G.; Hammond, C. J.; Moshiri, A.; Chen, R.; Tobin, M. D.; Batini, C.; Thomas, M. G.

2025-06-20 genetic and genomic medicine
10.1101/2025.06.18.25329836 medRxiv
Show 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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