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September 10, 2025Open Access

The rs10191329 Risk Allele Is Associated With Pronounced Retinal Layer Atrophy in Multiple Sclerosis

Key Points

Carriers of the rs10191329 risk allele exhibit accelerated retinal atrophy, implying increased neuroaxonal vulnerability in multiple sclerosis.
Each rs10191329 allele correlates with a 0.10% per year increase in retinal nerve fiber layer atrophy, with a significant p-value of less than 0.001.
Analysis based on optical coherence tomography scans from 183 patients with relapsing multiple sclerosis reveals genetic influences on retinal layer thinning.
This finding highlights the need for genetic stratification in neuroprotection-targeting clinical trials in multiple sclerosis patients.

Abstract

ABSTRACT Objective To investigate whether the rs10191329 risk allele in the DYSF–ZNF638 locus, which is implicated in central nervous system resilience rather than immune‐mediated pathology, is associated with retinal layer thinning, a biomarker of neuroaxonal damage in relapsing multiple sclerosis (RMS). Methods From a prospective observational study, we included RMS patients with ≥ 2 optical coherence tomography (OCT) scans, excluding eyes with optic neuritis during the observation period. DNA samples were genotyped using the Illumina Infinium Global Screening Array‐24 and variants imputed using the Haplotype Reference Consortium panel and Minimac4. Multivariable linear regression models were used to assess the association between rs10191329 risk allele number (rs10191329*A) and annualized rates of peripapillary retinal nerve fiber layer (aLpRNFL) and macular ganglion‐cell‐and‐inner‐plexiform‐layer (aLGCIPL) atrophy, adjusting for age, sex, MS‐specific variables, and 10 ancestry components. Results We included 183 RMS patients (mean age 35.9 years SD 9.6, 74.9% female, median EDSS 2.0 range 0–6.5, median observation 25 months 12–73, median OCT scans 3 2–5). Multivariable analyses revealed that each rs10191329*A allele was associated with a 0.10%/year increase in aLpRNFL (95% confidence interval CI 0.05–0.19, p < 0.001) and a 0.11%/year increase in aLGCIPL (95% CI 0.07–0.19, p < 0.001). The rs10191329 variant explained 8.9% of GCIPL atrophy and 8.2% of pRNFL atrophy variance. Interpretation Carriers of the rs10191329 risk allele show accelerated retinal atrophy, suggesting heightened neuroaxonal vulnerability in MS. While clinical implications are currently unclear, genetic stratification may be reasonable in clinical trials targeting neuroprotection.

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