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GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

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posted on 2023-09-21, 10:47 authored by International League Against Epilepsy Consortium on Complex Epilepsies, Remi Stevelink, Ciaran Campbell, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty, Colin P. Doherty, Hany El-NaggarHany El-Naggar, Austin LaceyAustin Lacey, Peter Widdess-Walsh, Quratulain Zulfiqar Ali

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. 

Funding

Details of funding agencies are on the paper

History

Data Availability Statement

The GWAS summary statistics data that support the findings of this study (for both multi-ancestry and European-only analyses) are publicly available at https://www.epigad.org/ and in the NHGRI-EBI GWAS Catalog at https://www.ebi.ac.uk/gwas/ (accession IDs: GCST90271608, GCST90271609, GCST90271610, GCST90271611, GCST90271612, GCST90271613, GCST90271614, GCST90271615, GCST90271616, GCST90271617, GCST90271618, GCST90271619 and GCST90271620). Individual-level GSA-MD v1.0 data for the Epi25 case samples and HKOS control samples are available in dbGaP/AnVIL under phs001489. v2.p2. GSA-MD v1.0 data for Genomic Psychiatry Cohort (GPC) control samples data will be made available in dbGAP/AnVIL under study phs002041. Individual-level SNP genotype data for other cohorts used as controls in the Epi25 analyses are accessible via an application through the THL Biobank portal (https://thl-biobank.elixir-finland.org/) for FINRISK, and in dbGaP/AnVIL under study accession numbers phs001642 (NIDDK IBDGC) and phs002018.v1.p1 (MGB Biobank) (see Supplementary Note for more details). Data relating to UK Biobank are available via the application to UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). The FinnGen data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB: release R6. The summary statistics of the Japanese GWAS in this study are publicly available from the National Bioscience Database Center (https://biosciencedbc.jp/en) under research ID: hum0014. We also accessed data from the following online database: www.DGidb.com (accessed on 26 November 2021). Source data are provided with this paper.

Comments

The original article is available at https://www.nature.com/

Published Citation

International League Against Epilepsy Consortium on Complex Epilepsies. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nat Genet. 2023;55(9):1471-1482.

Publication Date

31 August 2023

PubMed ID

37653029

Department/Unit

  • School of Pharmacy and Biomolecular Sciences
  • FutureNeuro Centre
  • Beaumont Hospital

Publisher

Springer Nature

Version

  • Published Version (Version of Record)