Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

Yixiang Zhou; Xindi Huang; Xiao She; Qin Hao; Zhikuan Mi; Yanling Yang

doi:10.1016/j.msard.2026.107410

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Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

Yixiang Zhou·Xindi Huang·Xiao She·Qin Hao·Zhikuan Mi·Yanling Yang

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Abstract

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. RESULTS: We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. CONCLUSIONS: This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.

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Humans Multiple Sclerosis Phenotype Epstein-Barr Virus Infections Genome-Wide Association Study Herpesvirus 4, Human Single-Cell Analysis Genetic Predisposition to Disease Quantitative Trait Loci Polymorphism, Single Nucleotide Mendelian Randomization Analysis Drug repositioning Epstein-Barr virus infections Mendelian randomization analysis Multiple sclerosis Single-cell gene expression analysis Journal Article

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Yixiang Zhou, Xindi Huang, Xiao She, Qin Hao, Zhikuan Mi, Yanling Yang. 2026-08-05. Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.. https://doi.org/10.1016/j.msard.2026.107410

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Journal Article resource Genetic Predisposition to Disease subject Genome-Wide Association Study subject Humans subject Journal Article subject Mendelian Randomization Analysis subject Multiple Sclerosis subject Phenotype subject Polymorphism, Single Nucleotide subject

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