Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk.

Mark Z Kos,Lucy Blondell,Koyle D Knape,Harald H H Göring,Charles Ákos Szabó,M Michelle Leland,Melanie A Carless

doi:10.3389/fgene.2021.714282

Abstract

In this study, we investigate the genetic determinants that underlie epilepsy in a captive baboon pedigree and evaluate the potential suitability of this non-human primate model for understanding the genetic etiology of human epilepsy. Archived whole-genome sequence data were analyzed using both a candidate gene approach that targeted variants in baboon homologs of 19 genes (n = 20,881 SNPs) previously implicated in genetic generalized epilepsy (GGE) and a more agnostic approach that examined protein-altering mutations genome-wide as assessed by snpEff (n = 36,169). Measured genotype association tests for baboon cases of epileptic seizure were performed using SOLAR, as well as gene set enrichment analyses (GSEA) and protein–protein interaction (PPI) network construction of top association hits genome-wide (p < 0.01; n = 441 genes). The maximum likelihood estimate of heritability for epileptic seizure in the pedigreed baboon sample is 0.76 (SE = 0.77; p = 0.07). Among candidate genes for GGE, a significant association was detected for an intronic SNP in RBFOX1 (p = 5.92 × 10–6; adjusted p = 0.016). For protein-altering variants, no genome-wide significant results were observed for epilepsy status. However, GSEA revealed significant positive enrichment for genes involved in the extracellular matrix structure (ECM; FDR = 0.0072) and collagen formation (FDR = 0.017), which was reflected in a major PPI network cluster. This preliminary study highlights the potential role of RBFOX1 in the epileptic baboon, a protein involved in transcriptomic regulation of multiple epilepsy candidate genes in humans and itself previously implicated in human epilepsy, both focal and generalized. Moreover, protein-damaging variants from across the genome exhibit a pattern of association that links collagen-containing ECM to epilepsy risk. These findings suggest a shared genetic etiology between baboon and human forms of GGE and lay the foundation for follow-up research.

Highlights

Epilepsy is a chronic, highly heterogeneous neurological disorder, with recurrent seizures being the diagnostic hallmark
Targeting baboon homologs of genes implicated in genetic generalized epilepsy (GGE) and related epilepsies in humans, 20,881 QC filtered single nucleotide polymorphisms (SNPs) from 19 genes were tested for association with epileptic seizure
The top association result is for a common intronic SNP in the gene RBFOX1 [chromosome 20 (NC_018171), base pair position 5,642,021 in intron 3 (ENSPANT00000033712.2); minor allele frequency (MAF) = 0.48], with an estimated β coefficient of 1.37 (SE = 0.30) and Bonferroni-corrected p = 0.016

Summary

Introduction

Highly heterogeneous neurological disorder, with recurrent seizures being the diagnostic hallmark. More promising are two rat models with presumed polygenic inheritance, Genetic Absence Rats from Strasbourg (GAERS) and Wistar Albino Glaxo rat from Rijswijk (WAG/Rij), (Gauguier et al, 2004; Rudolf et al, 2004) that have shown electroclinical and pathophysiological similarities to human GGE with absence epilepsy Despite these successes, translatability of these models is limited due to differences in neurodevelopment and the natural evolutionary histories of the species, as well as response to treatment, (Löscher, 2017) suggesting the need for alternate animal models that can further characterize the complex genetic architecture of GGE in humans and better identify new etiological pathways with novel therapeutic targets

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