GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epileps...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2023
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| _version_ | 1797111938028666880 |
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| author | Stevelink, R Campbell, C Chen, S Kariuki, S |
| author2 | International League Against Epilepsy Consortium on Complex Epilepsies |
| author_facet | International League Against Epilepsy Consortium on Complex Epilepsies Stevelink, R Campbell, C Chen, S Kariuki, S |
| author_sort | Stevelink, R |
| collection | OXFORD |
| description | Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment. |
| first_indexed | 2024-03-07T08:17:24Z |
| format | Journal article |
| id | oxford-uuid:93f2a86d-0e7a-4849-a34c-21df42baeaac |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:17:24Z |
| publishDate | 2023 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:93f2a86d-0e7a-4849-a34c-21df42baeaac2024-01-05T14:53:11ZGWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architectureJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:93f2a86d-0e7a-4849-a34c-21df42baeaacEnglishSymplectic ElementsSpringer Nature2023Stevelink, RCampbell, CChen, SKariuki, SInternational League Against Epilepsy Consortium on Complex EpilepsiesEpilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment. |
| spellingShingle | Stevelink, R Campbell, C Chen, S Kariuki, S GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture |
| title | GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture |
| title_full | GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture |
| title_fullStr | GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture |
| title_full_unstemmed | GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture |
| title_short | GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture |
| title_sort | gwas meta analysis of over 29 000 people with epilepsy identifies 26 risk loci and subtype specific genetic architecture |
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