Proteome-wide Mendelian randomization and colocalization analysis identify CD5 as a plasma protein associated with cerebral palsy

Cerebral palsy (CP), a neurodevelopmental disorder in children, remains incompletely understood, particularly regarding its etiology. The proteome offers potential therapeutic targets for a range of neurodevelopmental conditions. This investigation sought to explore the causal relationship between plasma proteins and CP risk through genome-wide Mendelian randomization (MR). Genetic instruments for 2923 plasma proteins were derived from extensive proteomic studies. Data on CP were obtained from publicly accessible datasets. Proteome-wide MR and colocalization analyses were employed to explore the causal impact of circulating proteins on CP. Protein-protein interaction and druggability assessments were performed to prioritize candidate therapeutic targets. Additionally, systematic MR analyses of healthy lifestyle factors and CP-associated proteins were executed to ascertain proteins that could serve as targets for intervention via lifestyle modifications. Genetically determined circulating levels of the plasma protein CD5 demonstrated significant associations with CP risk. Among the identified drug targets, baclofen has been used in the treatment of spastic CP, and CD5 levels can be modulated through healthy lifestyle interventions. This study identified CD5 as a circulating protein biomarker with strong causal evidence linking it to CP risk and highlighted it as a potential target for both pharmaceutical and lifestyle interventions, providing fresh perspectives on the mechanisms, prophylaxis, and management of CP.