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Distinct gene-set burden patterns underlie common generalized and focal epilepsies

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posted on 2023-11-22, 15:24 authored by Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Epi25 Collaborative, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty

Background: Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis.

Methods: The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls.

Findings: Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE.

Interpretation: Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies

Funding

Research Unit FOR-2715 of the German Research Foundation and the Fond Nationale de la Recherche of Luxembourg (DFG/FNR, grants INTER/DFG/17/11583046, Le1030/16-1, Sa434/6-1, No755/6-1, He5415/7-1, We4896/4-1)

National Human Genome Research Institute (NHGRI) UM1 HG008895; grant 5U01HG009088-02

National Heart, Lung, and Blood Institute (NHLBI)

German Academic Exchange Service (DAAD personal funding program Number 57214224)

FNR funding as part of the National Centre of Excellence in Research on Parkinson's disease (NCER-PD, FNR11264123)

FNR Open Access Fund

History

Data Availability Statement

The data/analyses presented in the current publication are based on the use of study data from the Epi25 Collaborative (http://epi-25.org/), available with controlled access through dbGaP (https://ncbi.nlm.nih.gov/gap/) and AnVIL project (https://anvilproject.org/data) with the accession number phs001489, and control exome data from dbGAP that are accessible with appropriate permissions under accession numbers phs000473 (Swedish Schizophrenia Study), phs001000 (Leicester UK Heart Study), phs000806 (Ottawa Hear Study), and phs000814 (Italian Atherosclerosis, Thrombosis, and Vascular Study). Supplemental data supporting the analyses presented are available on Mendeley Data (https://doi.org/10.17632/nmmz4wjvxk.1).

Comments

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

Published Citation

Koko M. et al. Distinct gene-set burden patterns underlie common generalized and focal epilepsies. EBioMedicine. 2021;72:103588.

Publication Date

24 September 2021

PubMed ID

34571366

Department/Unit

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

Research Area

  • Neurological and Psychiatric Disorders

Publisher

Elsevier BV

Version

  • Published Version (Version of Record)