Odkrycie nowego kandydata na lek przeciwpadaczkowy przy użyciu analizy genów w poszczególnych typach komórek mózgu: badanie genetyczne i kolokalzacyjne

Most antiseizure medicines act on a limited set of neuronal targets. Approximately a third of patients have treatment-resistant epilepsy, creating a need for mechanistically distinct drug targets. Human genetics can prioritise them, but epilepsy target-discovery has measured expression in plasma or bulk brain tissue and has yielded inconsistent candidate lists. Common-variant association for generalised epilepsy is enriched in neuronally expressed genes, so the cell type measured may determine which druggable targets are detectable. Genes at the genome-wide significant loci of the largest epilepsy meta-analysis were assessed by drug-target Mendelian randomisation (MR). A gene was retained only where the expression and disease signals colocalised on a single causal variant at a posterior probability above 0.8. Each gene was assessed across inhibitory neurons, excitatory neurons, four glial cell types, and bulk cortex, with fine-mapping and directional testing in FinnGen. Of the 23 prioritised genes screened, MR nominated ten and colocalisation retained 2. colocalised with generalised epilepsy above the threshold in inhibitory neurons alone. Higher expression was associated with lower risk (posterior 0.95, odds ratio (OR) 0.64, and = 2.5 × 10), with a weaker, directionally concordant sub-threshold signal in oligodendrocytes (posterior 0.53). The colocalising variant is shared with the neighbouring ( = 0.975), so the two genes cannot be separated on genetic evidence alone. In the bulk cortex, carried a strong expression signal mapping to a different causal variant, with no colocalisation. colocalised across inhibitory neurons, excitatory neurons, and bulk cortex for generalised epilepsy and was associated with increased risk (OR 1.46). Both directions reproduced at the matched generalised-epilepsy endpoint in FinnGen, where was protective and was risk-increasing. The colocalisation did not reproduce there, so FinnGen supports the direction of effect and not the shared-variant evidence. In epilepsy, the cellular compartment in which expression is measured can determine whether a drug-target signal is detected, so analyses restricted to plasma or bulk tissue may miss cell-type-restricted targets such as . The demonstration rests on this single locus. Cell-type-resolved colocalisation prioritises , which cannot be separated from , as a candidate for functional investigation, with being a genetically supported but pharmacologically intractable second locus.