GMDS and OPTN-related Open Angle Glaucoma

This summary reviews the association between GMDS (HGNC:4369) and OPTN‑related open angle glaucoma (MONDO_0100553). Two independent large-scale studies have identified statistically significant associations between common variants in GMDS and risk for primary open‑angle glaucoma. The first genome‑wide association study investigated an Australian cohort with 1,155 cases (PMID:25173105) and multiple replication cohorts totaling over 8,000 subjects. In these cohorts, the risk allele at GMDS (rs11969985[G]) demonstrated an odds ratio of 1.31 with genome‑wide significance, thereby implicating GMDS in disease susceptibility. This evidence strongly supports the gene‑disease link by virtue of its robust statistical backing and biological plausibility. Expression studies in ocular tissues further corroborate the relevance of GMDS in the pathobiology of glaucoma.

The second study evaluated pharmacogenetic associations in a cohort of 135 patients with primary open‑angle glaucoma (PMID:27862086). In this investigation, the GMDS variant rs9503012 C>T was associated with an improved intra‑ocular pressure response to latanoprost, suggesting that genetic variation in GMDS may impact treatment outcomes. Although the primary focus of this study was on treatment response rather than disease causation per se, the findings further reinforce the clinical relevance of GMDS in the context of glaucoma. Both studies, despite differences in design, converge on the role of GMDS in the disease process. The convergence of genetic association signals across independent cohorts strengthens the confidence in these findings.

While classic familial segregation data is not available for GMDS in relation to glaucoma, the collective case–control and pharmacogenetic data provide a compelling rationale for its involvement. No direct family studies demonstrating co‑segregation of rare coding variants have been reported. Instead, the evidence is derived from statistically robust associations in large cohorts and from observed genotype‑phenotype correlations. The absence of traditional family data is offset by the large sample sizes and consistency of the findings across diverse populations. Hence, the weight of the genetic evidence lies in the multiple independent associations rather than in segregation analysis. This association, therefore, is evaluated from a perspective more typical of complex trait genetics.

In terms of variant-level details, the reported associations are driven by common single nucleotide polymorphisms rather than rare coding changes. Although no HGVS‐formatted coding variant (i.e. one starting with “c.” and including a protein change) has been identified for GMDS in these studies, the SNP associations remain highly informative for population‐based risk assessment. Future research might identify additional coding changes that further elucidate the pathway from genotype to phenotype. For now, the evidence relies on common variant analyses, which are integral to understanding complex disease predisposition. Such evidence remains valuable in precision medicine and risk stratification.

Functional studies specific to GMDS in ocular tissues have been limited. Nevertheless, expression profiling confirmed that GMDS is expressed in the human retina, optic nerve, and trabecular meshwork, which are key tissues implicated in glaucoma pathogenesis. This observation, while not constituting a direct functional assay, supports the biological plausibility of the genetic findings. Furthermore, the pharmacogenetic study implies a functional impact of GMDS variation on intra‑ocular pressure modulation. However, detailed mechanistic experiments (e.g., cellular or animal models) remain to be performed to fully establish the mechanism of pathogenicity. Thus, from a functional perspective, the evidence remains supportive but not definitive.

In conclusion, the convergence of robust genetic association studies and complementary expression data provides strong evidence for a role of GMDS in OPTN‑related open angle glaucoma. Although the evidence is based on common variant associations without classical segregation or detailed functional follow‑up, it remains clinically actionable for diagnostic decision‑making and may guide future research. Key take‑home: GMDS is a promising genetic marker for risk and therapeutic response in open angle glaucoma, warranting further functional and translational studies.

References

• Nature Genetics • 2014 • Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open‑angle glaucoma PMID:25173105
• Journal of Clinical Pharmacy and Therapeutics • 2017 • Correlations of AFAP1, GMDS and PTGFR gene polymorphisms with intra‑ocular pressure response to latanoprost in patients with primary open‑angle glaucoma PMID:27862086

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