EOS is a complex disorder with unclear etiology, in which genetic factors may play a potential role. However, previous GWASs, based on heterogeneous design, have yielded inconsistent findings, and the genetic mechanisms underlying EOS remain elusive.

The EOS cohort comprised UKB participants whose age at first-ever stroke ranged from 18 to 50 years. GWAS was performed using quality-controlled genotype array and imputation data. TWAS based on GTEx dataset was conducted to identify EOS-associated gene expression pattern across 49 tissues. Furthermore, scTWAS was performed using a comprehensive human brain single-cell atlas to determine cell type–specific gene expression pattern of EOS across 7 major cell types and 64 subtypes. Expression genetic risk scores (eGRS) were calculated for prioritized genes derived from GWAS and scTWAS, and proteomic associations between eGRS and 2,919 plasma proteins were subsequently examined.

A total of 1,970 EOS cases and 322,084 controls were included in final analysis. GWAS did not identify any genome-wide significant variants across all stroke subtypes. TWAS identified tissue-specific associations of GPBP1 gene for hemorrhagic EOS in putamen (P_FDR = 0.0303) and whole blood (P_FDR = 0.0292). scTWAS further revealed significant associations of GPBP1 in astrocytes (P_FDR = 0.0372), excitatory neurons (P_FDR = 0.0101), and three excitatory neuron subtypes. Proteomic analysis of GPBP1 eGRS revealed a significant association with plasma SCGB3A1 level (β = -0.009,P_FDR = 0.0002). Causal inference of GPBP1 was supported by summary-based Mendelian randomization, HEIDI testing, and colocalization analysis.