Assessing the causal relationship between the plasma proteome and epilepsy: A Mendelian randomization study

Area of Science:

• Neuroscience
• Genetics
• Proteomics

Background:

• Epilepsy pathophysiology requires understanding circulating protein roles for novel therapeutic targets.
• Mendelian randomization (MR) is a key method for assessing causal links between proteins and disease risk.

Purpose of the Study:

• To systematically evaluate potential causal relationships between the plasma proteome and epilepsy.
• To identify candidate proteins for future experimental validation in epilepsy research.

Main Methods:

• A multistage MR framework analyzed 4907 plasma proteins against epilepsy, generalized epilepsy (GE), and focal epilepsy (FE) phenotypes.
• Proteome-wide MR, Summary-data-based MR (SMR), and colocalization analyses were employed.
• Alternative pQTL resources were used to assess the robustness of findings.

Main Results:

• A proteome-wide screen identified nominal associations between proteins and epilepsy risk (P-IVW < 0.01).
• SMR analysis supported candidates including CRABP2, CD300C (epilepsy), GM2A (FE), and PCBD1 (GE).
• Colocalization analysis showed limited evidence for shared causal variants, indicating complex genetic architecture.

Conclusions:

• No definitively causal proteins were identified, but a prioritized list of candidates (e.g., CRABP2, CD300C, GM2A, PCBD1) emerged.
• These candidates, involved in neurodevelopmental, immune, and metabolic pathways, warrant further experimental validation.
• Cross-validation across pQTL datasets highlights the importance of replication in epilepsy research.