Identification of potential biomarkers and therapeutic targets for cerebral venous thrombosis

Cerebral venous thrombosis (CVT) is an uncommon yet potentially life-threatening subtype of stroke that predominantly affects younger individuals. This study aimed to systematically identify and validate druggable genes associated with CVT susceptibility using Mendelian randomization (MR) approaches.

We integrated two large-scale expression quantitative trait loci (eQTLs) datasets - eQTLGen (peripheral blood) and PsychENCODE (brain tissue) - as exposures, with CVT genome-wide association study (GWAS) summary statistics from FinnGen serving as the outcome. A two-sample MR (TSMR) framework was employed, supported by sensitivity analyses, summary-data-based MR (SMR), and Bayesian colocalization. Functional enrichment, single-cell analyses, drug prediction, and molecular docking were further performed to explore biological relevance and therapeutic potential.

TSMR identified 19 candidate genes from blood eQTLs after false discovery rate (FDR) correction; two were excluded due to pleiotropy, leaving 17, among which 10 were supported by SMR and colocalization. An additional nominally significant gene (ZP3) was detected from brain tissue. Of these, IL18, BMPR2, and COMT exhibited the strongest evidence. Functional annotation implicated these genes in cytokine signaling, cellular adhesion, and coagulation pathways. Single-cell RNA sequencing localized their expression mainly to monocytes, dendritic cells, and natural killer cells. Drug repurposing and docking analysis suggested potential inhibitory interactions between IL18 and glucocorticoids/pioglitazone, and between BMPR2 and iloprost.

This study reveals novel gene networks potentially involved in CVT pathogenesis and prioritizes IL18, BMPR2, and COMT as promising candidates for future therapeutic development. Nonetheless, these findings are based on genetic inference and require further mechanistic and clinical validation.