Proteome-wide Mendelian randomization and colocalization analysis identify CD5 as a plasma protein associated with
Chao Bai1, Mingbo Hu, Hong Zhao
1Cerebral Palsy Center in Neurosurgery, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Insights
This study identifies CD5 as a key plasma protein linked to cerebral palsy (CP) risk. Modulating CD5 offers potential for new pharmaceutical and lifestyle interventions for CP.
Area of Science:
- Neuroscience and Genetics
- Proteomics and Biomarker Discovery
Background:
- Cerebral palsy (CP) is a common childhood neurodevelopmental disorder with complex and often unknown causes.
- The plasma proteome presents a promising avenue for identifying therapeutic targets in neurodevelopmental conditions.
Purpose of the Study:
- To investigate the potential causal links between circulating plasma proteins and the risk of developing cerebral palsy.
- To identify novel protein biomarkers and therapeutic targets for CP through proteome-wide Mendelian randomization.
Main Methods:
- Genome-wide Mendelian randomization (MR) was used with genetic instruments for 2923 plasma proteins and CP data.
- Proteome-wide MR, colocalization, protein-protein interaction, and druggability analyses were performed.
- MR analyses also assessed healthy lifestyle factors in relation to CP-associated proteins.
Main Results:
- The plasma protein CD5 showed a significant, genetically determined association with increased cerebral palsy risk.
- Baclofen, a drug used for spastic CP, was identified as a potential therapeutic targeting CD5.
- Healthy lifestyle interventions were found to modulate CD5 levels.
Conclusions:
- CD5 is a causally implicated circulating protein biomarker for cerebral palsy risk.
- CD5 represents a potential therapeutic target for both pharmaceutical interventions and lifestyle modifications.
- Findings offer new insights into CP mechanisms, prevention, and management strategies.
Abstract:
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.
