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

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

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.714282

DOI=10.3389/fgene.2021.714282

ISSN=1664-8021

ABSTRACT=<p>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 (<italic>n</italic> = 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 (<italic>n</italic> = 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 <italic>(p</italic> &lt; 0.01; <italic>n</italic> = 441 genes). The maximum likelihood estimate of heritability for epileptic seizure in the pedigreed baboon sample is 0.76 (SE = 0.77; <italic>p</italic> = 0.07). Among candidate genes for GGE, a significant association was detected for an intronic SNP in <italic>RBFOX1 (p</italic> = 5.92 × 10<sup>–6</sup>; adjusted <italic>p</italic> = 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.</p>