Potential causal link between antiseizure medication targets and cognitive function: A mendelian randomization study

Abstract

A common strategy for treating epilepsy is the use of antiseizure medications (ASMs). However, ASMs usually raise concerns about accompanying side effects on the cognitive function of patients. Understanding the causal relationship between ASMs targets and cognitive function is crucial for developing therapeutic strategies that mitigate cognitive side effects while effectively managing seizures. This study aimed to explore the relationship between expression of ASMs targets and cognitive function through Mendelian randomization (MR). ASMs targets were collected from the Drugbank database, and genetic instruments for these targets were identified from publicly available expression quantitative trait loci (eQTL) data of blood samples. They underwent two-sample MR and summary data-based MR analyses with two genome-wide association study (GWAS) datasets on cognitive outcomes. Further sensitivity analyses such as assessment of horizontal pleiotropy, colocalization, and multiple tissue sensitivity were performed to confirm the discovered MR associations. A total of 160 targets for 38 approved ASMs were collected. Among these target genes, 3789 SNPs with p-value <5.0e-8 in whole blood were extracted from the eQTL dataset. Results from the MR analysis indicated that carbonic anhydrase 13 (CA13) has a potential causal link with both cognitive performance and fluid intelligence score, independent of epilepsy. The expression of CA13, an ASM target, is significantly associated with cognitive function, highlighting the potential for this target to influence cognitive outcomes during epilepsy treatment. While the findings suggest CA13 could be a potential modulator of cognitive function, MR cannot definitively confirm causality, and further functional studies are required to validate this association and elucidate the underlying mechanisms.