Integrating a multi-omics strategy framework to screen potential targets in cognitive impairment-related epilepsy

Epilepsy is a prevalent neurological disorder that affects over 70 million individuals worldwide and is often associated with cognitive impairments. Despite the widespread impact of epilepsy and cognitive impairments, the genetic basis and causal relationships underlying these conditions remain uncertain, prompting us to conduct a comprehensive investigation into the molecular mechanisms involved. In this study, we utilized statistical data from the third National Health and Nutrition Examination Survey (NHANES III) to evaluate correlation and large-scale pan-phenotype genome-wide association study (GWAS) data to establish genetic correlation and causality. Leveraging multi-omics datasets, we performed a comprehensive post-analysis that included variant prioritization, gene analysis, tissue and cell type enrichment, and pathway annotation. An integrated strategy—multi-trait analysis of GWAS (MTAG), transcriptome-wide association study (TWAS), summary-data-based Mendelian Randomization (SMR), and protein quantitative trait locus (pQTL)-MR—was performed to investigate the shared genetic architecture. Based on multiple orthogonal lines of evidence, we thereby identified 40 single nucleotide polymorphisms (SNPs) and 85 genes common to both conditions. Additionally, we optimized candidate genes such as GNAQ, FADS1, and PTK2 by single-cell expression analysis and molecular pathway mechanisms, thereby highlighting potential shared genetic pathways. These findings elucidate the genetic interplay and co-occurring mechanisms between epilepsy and cognitive impairments, providing crucial insights for future research and therapeutic strategies.