Multi-Ancestry Genome-Wide Association with Fine-Mapping Identifies Novel Loci for Pigment Dispersion Syndrome and...

Pigment dispersion syndrome and pigmentary glaucoma are important causes of ocular hypertension and glaucomatous optic neuropathy, yet their genetic determinants remain incompletely defined, particularly across diverse ancestries. This study aimed to use a large multi-ancestry cohort from the All of Us Research Program to investigate the genetic basis of pigment dispersion syndrome and pigmentary glaucoma.

Case-control study.

In total, 572 cases and 37 808 controls with array genotyping and 537 cases and 35 493 controls with whole-genome sequencing.

Using electronic health record phenotyping in the All of Us Research Program, we performed multi-ancestry genome-wide association analyses using both array-based data and whole-genome sequencing-based data, comparing patients with pigment dispersion syndrome or pigmentary glaucoma to those without either condition. We also performed Firth penalized regression and Fisher analyses, and we performed principal component analyses to assess effect sizes across genetic ancestries. We applied statistical fine-mapping, examined for cross-trait overlap, and assessed expression quantitative trait locus associations for lead variants.

P values and odds ratios of lead loci from genome-wide association analyses; size of credible sets determined from fine-mapping; allele frequency of lead variants in cases, controls, and the general population; expression quantitative trait loci effect size and P values linking lead variants to gene expression.

We identified 4 loci reaching genome-wide significance across analyses, including signals near EPHA7 (which mediates cell-cell signaling), within TYR (involved in melanin synthesis and replicated from prior studies), within LINC01138, and near OTX2. Statistical fine-mapping refined 3 of these loci to single-variant 95% credible sets and narrowed the TYR locus to small credible sets, prioritizing possible causal variants. Effect estimates were broadly consistent across genetic ancestry clusters. Lead variants showed regulatory evidence in expression quantitative trait locus, including reduced EPHA7 expression.

These findings implicate both melanogenesis and cell-cell adhesion and signaling pathways in pigment dispersion syndrome and pigmentary glaucoma.

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