Stroke. 2026 Mar 2. doi: 10.1161/STROKEAHA.125.053747. Online ahead of print.
ABSTRACT
BACKGROUND: Moyamoya disease (MMD) has a strong genetic basis, with the rare RNF213 variant (rs112735431) representing a major risk factor, while the broader genetic architecture and disease-relevant vascular cell types remain incompletely understood.
METHODS: We conducted a genome-wide association study in Japanese individuals (n=47 656; 401 MMD cases and 47 255 controls). Population-level features at MMD risk loci were examined by regional allele frequency and haplotype analyses. We performed single-nucleus RNA-seq of superficial temporal arteries from patients with MMD (n=3). Cell type-specific enrichment of genome-wide association study signals was assessed using the Single-Cell Disease Relevance Score. Endothelial signatures were validated by integration with publicly available single-cell data sets from controls (n=5) and immunohistochemistry for candidate markers (n=1).
RESULTS: Beyond rs112735431, we identified a genome-wide significant signal in the HDAC9-TWIST1 region (P=3.3×10-14; odds ratio, 1.77). Conditional analysis on rs112735431 revealed a protective RNF213 missense variant, p.Asn1331Gly (rs8074015; P=3.7×10–9; odds ratio, 0.53), whose minor allele was mutually exclusive with rs112735431-A on haplotypes. Population analysis revealed geographic variation and extended haplotype structure of the rs112735431-A allele in Japan. Single-nucleus RNA-seq identified a mesenchymal-like endothelial cell (MEC) population with selective FN1 expression. Genome-wide association study-prioritized disease genes were strongly enriched in MECs. MECs showed mesenchymal pathway activation with a regulatory program distinct from canonical endothelial states. The proportion of MECs was markedly increased in MMD (72% versus 28% in controls), and FN1 expression in endothelial regions was confirmed by immunohistochemistry.
CONCLUSIONS: Our findings identify a protective RNF213 variant that is mutually exclusive with the known rs112735431-A allele. Genetic risk converges on an MEC state markedly expanded in MMD.
PMID:41766532 | DOI:10.1161/STROKEAHA.125.053747
