Drug-resistant epilepsy classified by a phenotyping algorithm associates with NTRK2

Objective: Up to 40% of patients with epilepsy become drug resistant (DRE). Genetic factors are likely to play a role. While efforts have focused on the transporter and target hypotheses, neither of them fully explains the pan-pharmacoresistance seen in DRE. Materials and methods: In this study, we developed and used a phenotyping algorithm for the identification of DRE, responders, and epilepsy-free controls that were sequenced using a gene panel developed by the Pharmacogenomics Research Network (PGRN), which includes 82 genes involved in drug response. We tested the transporter hypothesis of DRE, the association between drug resistance and variants in the ATP-binding cassette family of genes previously associated with DRE, and also investigated potential new genetic factors. Results: In the analysis of DRE vs controls, NTRK2 was significantly associated with DRE (rs76950094; P = 1.19 × 10⁻⁷ and gene-based P-value = 1.67 × 10⁻⁴). NTRK2 encodes TrkB, which is involved in the development and maturation of the central nervous system, and increased activation of TrkB signaling is suggested to promote epilepsy. Conclusion: Although the role of NTRK2 in DRE needs to be elucidated, these results support alternative mechanisms underlying DRE, complementary to the existing hypotheses, that should be evaluated.