Genetic susceptibility to cerebral palsy involves complement system-mediated neuronal development and plasticity...

Cerebral palsy (CP) is a complex neurological disorder characterized by motor and postural impairments, often stemming from prenatal or perinatal brain injury. Despite extensive research, the precise genetic mechanisms underlying CP remain elusive.Here, we employed genome-wide Summary-data based MR (SMR) and Mendelian randomization (MR) analysis to investigate the potential causal role of genes within the complement system in neuronal development and plasticity (CSNDP) pathway in CP pathogenesis. Leveraging summary-level data from large-scale GWAS and quantitative trait locus (QTL) studies, we assessed the associations of CSNDP-related gene expression, DNA methylation, and protein abundance with CP susceptibility.Our analysis identified several putatively causal genes associated with CP risk, including CX3CL1 and TYRO3, both implicated in neuroinflammation and synaptic modulation. Colocalization analysis provided strong evidence for shared genetic variants driving the association of CX3CL1 and TYRO3 with CP risk. Furthermore, druggability assessment revealed the potential therapeutic targets of CX3CL1 and TYRO3, supporting their relevance in CP treatment strategies. Phenome-wide association studies demonstrated no significant adverse effects of drugs targeting CX3CL1 and TYRO3 on other disease traits, suggesting their safety profile.Our findings shed light on the molecular underpinnings of CP and highlight the potential of targeted interventions within the CSNDP pathway.