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

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).

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.

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.

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.