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Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk
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 c...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417722/ https://www.ncbi.nlm.nih.gov/pubmed/34490042 http://dx.doi.org/10.3389/fgene.2021.714282 |
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author | Kos, Mark Z. Carless, Melanie A. Blondell, Lucy Leland, M. Michelle Knape, Koyle D. Göring, Harald H. H. Szabó, Charles Ákos |
author_facet | Kos, Mark Z. Carless, Melanie A. Blondell, Lucy Leland, M. Michelle Knape, Koyle D. Göring, Harald H. H. Szabó, Charles Ákos |
author_sort | Kos, Mark Z. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8417722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84177222021-09-05 Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk Kos, Mark Z. Carless, Melanie A. Blondell, Lucy Leland, M. Michelle Knape, Koyle D. Göring, Harald H. H. Szabó, Charles Ákos Front Genet Genetics 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. Frontiers Media S.A. 2021-08-20 /pmc/articles/PMC8417722/ /pubmed/34490042 http://dx.doi.org/10.3389/fgene.2021.714282 Text en Copyright © 2021 Kos, Carless, Blondell, Leland, Knape, Göring and Szabó. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Kos, Mark Z. Carless, Melanie A. Blondell, Lucy Leland, M. Michelle Knape, Koyle D. Göring, Harald H. H. Szabó, Charles Ákos Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk |
title | Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk |
title_full | Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk |
title_fullStr | Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk |
title_full_unstemmed | Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk |
title_short | Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk |
title_sort | whole genome sequence data from captive baboons implicate rbfox1 in epileptic seizure risk |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417722/ https://www.ncbi.nlm.nih.gov/pubmed/34490042 http://dx.doi.org/10.3389/fgene.2021.714282 |
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