Whole-Genome Sequencing to Identify Biological Processes Associated with Epilepsy in Baboons
Abstract number :
3.494
Submission category :
2. Translational Research / 2D. Models
Year :
2025
Submission ID :
1485
Source :
www.aesnet.org
Presentation date :
12/8/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Melanie Carless, PhD – University of Texas San Antonio
Charles Szabo, MD – UT Health San Antonio
Mark Kos, PhD – University of Texas Rio Grande Valley
Rationale: While rodent models of epilepsy have been instrumental in developing antiseizure medications, about a third of patients with epilepsy do not respond to these. In part, this may be due to the inability of these rodent models to fully capture the genetic complexity of human genetic generalized epilepsies (GGEs). Baboons (genus Papio) are highly suitable genetic models for humans, as their genomes are more similar to humans than those of less closely related model organisms, including rodents, and they share neuroanatomical, biochemical, and physiological features stemming from their close phylogenetic relationship. These primates exhibit naturally occurring, highly heritable epilepsy, displaying strong electroclinical similarities with human GGE, specifically juvenile myoclonic epilepsy. To evaluate the potential of baboons as a preclinical model for epilepsy, we therefore sought to identify genetic variation associated with seizures in baboons, for comparison to human studies.
Methods: We performed genome-wide association (GWA) analysis of archived whole-genome sequence (WGS) data for 147 epileptic baboons and 238 well-characterized controls to identify potential epilepsy-associated risk genes. We subsequently performed pathway analyses using the program DAVID on gene lists with P< 0.005 (n=1,053 genes), testing gene sets that have been adjusted for the Papio anubis genome. We defined significant enrichment of KEGG pathways and three gene ontology (GO) categories (Biological Processes, BP; Cellular Component, CC; and Molecular Function, MF) using a false discovery rate (FDR) of 0.05.
Results: We did not identify any statistically significant associations with epilepsy in our baboon cohort using an FDR< 0.05. Our most significant association was located within a non-coding RNA (ENSPANG00000042050; P=5.83-7) and some of our top hits are within or near genes that have been previously linked to epilepsy phenotypes (e.g., ACSM5, SLC7A11, MAPRE2). The top KEGG enriched pathways were related to cardiomyopathies (FDR=8.63x10-4) and calcium signaling (FDR=1.40x10-2). The strongest enrichment for the CC GO category was glutamatergic signaling (FDR=7.91x10-8), with other brain-related significant enrichment seen for axon (FDR=1.73x10-3), GABA-ergic synapse (FDR=4.67x10-3) and post-synaptic density membrane (FDR=8.45x10-3) components, amongst others. For BP, the strongest association was seen for modulation of chemical synaptic transmission (FDR=5.94x10-3). Table 1 shows the most significant associations from KEGG pathways and GO analysis.
Conclusions: We identified nominally significant associations between human-epilepsy genes and baboon epilepsy. In addition, several pathways, cellular components and biological pathways relevant to brain development and/or epilepsy were enriched in our genome-wide association. These findings suggest that genetic variation associated with baboon epilepsy is within genes and pathways that overlaps with human epilepsy studies. The significance of this work suggests that the baboon provides a strong genetic background for preclinical modeling of epilepsy.
Funding: This work was supported by NIH/NINDS:1R56NS135399-01.
Translational Research