bioRxiv : the preprint server for biology · 2026
Variant-to-gene mapping identifies ARHGEF12 as a primary open-angle glaucoma effector gene operating within retinal ganglion cells.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Vrathasha Vrathasha, Pahl Matthew C, Pippin James A, Nikonov Sergei, He Jie, Halimitabrizi Mina, Moksha Laxmi, Salowe Rebecca, Edziah Amy-Ann, Bradford Yuki, Zhu Yan, Gudiseva Harini V, Chavali Venkata R M, da Costa Bruna Lopes, Berry Anne Marie, Quinn Peter M J, Cui Qi N, Miller-Ellis Eydie, Sankar Prithvi S, Ross Ahmara G, Addis Victoria, Verma Shefali S, Wells Andrew D, Grant Struan F A, O'Brien Joan M
Аннотация
Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness, has a strong genetic basis. The Primary Open-Angle African Ancestry Glaucoma Genetics study previously identified 46 risk loci. To pinpoint causal variants and their corresponding effector genes, we analyzed gene expression, chromatin accessibility, and conformation in two ocular cell-types: trabecular meshwork cells (hTMCs) and retinal ganglion cells derived from induced pluripotent stem cells (hiPSC-RGCs). We identified 24 candidate genes in hTMCs and 56 in hiPSC-RGCs. The ARHGEF12 gene was selected for further validation because it was nominated by local and distal promoter interactions in both cell-types and has reproducible prior evidence of its association with POAG. While its role in hTMCs is established, its function in RGCs is unclear. hiPSC-RGCs generated from a POAG donor homozygous for the risk allele showed reduced ARHGEF12 expression, altered morphology, and disrupted neuronal activity. This framework enables functional evaluation of additional POAG risk variants.