Large-scale Genetic Studies Discover an Allelic Spectrum of Genetic Risk Factors for the Epilepsies
Abstract number :
2.039
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
841
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Siwei Chen, PhD – Massachusetts General Hospital
Remi Stevelink, PhD – University Medical Center Utrecht
Ciarán Campbell, PhD – Genomics England
Bobby Koeleman, PhD – University Medical Center Utrecht
Gianpiero Cavalleri, PhD – Royal College of Surgeons in Ireland
Benjamin Neale, PhD – Massachusetts General Hospital
Samuel Berkovic, MD, FRS – University of Melbourne
Rationale: The epilepsies are a group of heterogeneous disorders and follow a complex pattern of inheritance where a number, and/or a combination, of rare and common variants confer risk for the disorder.
Methods: Here, through an international collaborative effort via the Epi25, we present a whole-exome sequencing (WES) study of >54,000 individuals, composed of 20,979 deep-phenotyped patients with diverse epilepsies and 33,444 controls spanning six genetic ancestries. We investigated ultra-rare variant (URV) risk for the epilepsies using a hypothesis-free approach that evaluates the excess of URVs in epilepsy across the entire exome and for each major subtype of epilepsy.
Results: With the unprecedented sample size, we discovered six individual genes and three gene sets at stringent exome-wide significance, revealing both shared and distinct rare variant risk for different subtypes of epilepsies. In parallel, we performed copy number variant calling on the same dataset and genome-wide association study (GWAS) in partnership with the International League Against Epilepsy (ILAE) consortium. The GWAS meta-analyzed >29,000 subjects with common epilepsies and >52,000 controls, and discovered 26 genome-wide significant common risk loci implicating 29 likely causal genes. Collectively, these results constitute an allelic spectrum of genetic variation contributing to epilepsy, greatly expanding our view of the genetic landscape of this highly heterogenous disorder. Meanwhile, by integrating all these findings – from across rare single nucleotide/short indel-, copy number-, and common variants – we identified convergence between different genetic risk factors in the same genes, suggesting that the wide range of risk loci likely points to a much smaller set of genes with at least partially shared etiological processes. More broadly, comparing our results to other large-scale WES studies, we found strong evidence for a genetic overlapping between epilepsy and other neurodevelopmental disorders.
Conclusions: This latest package of our studies, representing the largest-scale genetic investigation into the epilepsies to date, suggested that well-powered and well-phenotyped association analysis may help elucidate the complex genetic architecture underlying the epilepsies.
Funding: National Human Genome Research Institute (NHGRI)
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Neurological Disorders and Stroke (NINDS)
Genetics