TY - JOUR
T1 - The role of common genetic variation in presumed monogenic epilepsies
AU - The Epi4K Collaborative
AU - Genomics England Research Consortium
AU - The Epi25 Collaborative
AU - Campbell, Ciarán
AU - Leu, Costin
AU - Feng, Yen Chen Anne
AU - Wolking, Stefan
AU - Moreau, Claudia
AU - Ellis, Colin
AU - Ganesan, Shiva
AU - Martins, Helena
AU - Oliver, Karen
AU - Boothman, Isabelle
AU - Benson, Katherine
AU - Molloy, Anne
AU - Brody, Lawrence
AU - Michaud, Jacques L.
AU - Hamdan, Fadi F.
AU - Minassian, Berge A.
AU - Lerche, Holger
AU - Scheffer, Ingrid E.
AU - Sisodiya, Sanjay
AU - Girard, Simon
AU - Cosette, Patrick
AU - Delanty, Norman
AU - Lal, Dennis
AU - Cavalleri, Gianpiero L.
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022/7
Y1 - 2022/7
N2 - Background: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings: Cases of presumed monogenic severe epilepsy had an increased PRS for ‘all epilepsy’ (p<0.0001), ‘focal epilepsy’ (p<0.0001), and ‘GGE’ (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. Interpretation: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. Funding: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.
AB - Background: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings: Cases of presumed monogenic severe epilepsy had an increased PRS for ‘all epilepsy’ (p<0.0001), ‘focal epilepsy’ (p<0.0001), and ‘GGE’ (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. Interpretation: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. Funding: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.
KW - DEEs
KW - Epilepsy
KW - Genetic diagnostics
KW - PRS
UR - http://www.scopus.com/inward/record.url?scp=85131451531&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131451531&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2022.104098
DO - 10.1016/j.ebiom.2022.104098
M3 - Article
C2 - 35679801
AN - SCOPUS:85131451531
SN - 2352-3964
VL - 81
JO - EBioMedicine
JF - EBioMedicine
M1 - 104098
ER -