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...
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| Format: | Article |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.714282/full |
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| author | Mark Z. Kos Melanie A. Carless Melanie A. Carless Lucy Blondell M. Michelle Leland Koyle D. Knape Harald H. H. Göring Charles Ákos Szabó Charles Ákos Szabó |
| author_facet | Mark Z. Kos Melanie A. Carless Melanie A. Carless Lucy Blondell M. Michelle Leland Koyle D. Knape Harald H. H. Göring Charles Ákos Szabó Charles Ákos Szabó |
| author_sort | Mark Z. Kos |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-16T06:22:31Z |
| format | Article |
| id | doaj.art-ea7bcb588835406e8f7b81932b91751b |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-16T06:22:31Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-ea7bcb588835406e8f7b81932b91751b2022-12-21T22:41:05ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-08-011210.3389/fgene.2021.714282714282Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure RiskMark Z. Kos0Melanie A. Carless1Melanie A. Carless2Lucy Blondell3M. Michelle Leland4Koyle D. Knape5Harald H. H. Göring6Charles Ákos Szabó7Charles Ákos Szabó8Department of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United StatesDepartment of Biology, The University of Texas at San Antonio, San Antonio, TX, United StatesBrain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United StatesDepartment of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United StatesLaboratory Animal Research, UT Health San Antonio, San Antonio, TX, United StatesDepartment of Neurology, UT Health San Antonio, San Antonio, TX, United StatesDepartment of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United StatesDepartment of Neurology, UT Health San Antonio, San Antonio, TX, United StatesSouth Texas Comprehensive Epilepsy Center, San Antonio, TX, United StatesIn 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.714282/fullwhole-genome sequenceassociation testPapiobaboonidiopathic generalized epilepsyepilepsy |
| spellingShingle | Mark Z. Kos Melanie A. Carless Melanie A. Carless Lucy Blondell M. Michelle Leland Koyle D. Knape Harald H. H. Göring Charles Ákos Szabó Charles Ákos Szabó Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk Frontiers in Genetics whole-genome sequence association test Papio baboon idiopathic generalized epilepsy epilepsy |
| 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 | whole-genome sequence association test Papio baboon idiopathic generalized epilepsy epilepsy |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.714282/full |
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