1. Unraveling the shared genetics of common epilepsies and general cognitive ability.
- Author
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Karadag N, Hagen E, Shadrin AA, van der Meer D, O'Connell KS, Rahman Z, Kutrolli G, Parker N, Bahrami S, Fominykh V, Heuser K, Taubøll E, Ueland T, Steen NE, Djurovic S, Dale AM, Frei O, Andreassen OA, and Smeland OB
- Subjects
- Humans, Cognition physiology, Cognitive Dysfunction genetics, Cognitive Dysfunction physiopathology, Female, Male, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Phenotype, Genome-Wide Association Study, Epilepsy genetics
- Abstract
Purpose: Cognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown., Methods: We investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes 'all epilepsy', focal epilepsies and genetic generalized epilepsies (GGE), as well as specific subtypes. We functionally annotated the identified loci using several biological resources and validated the results in independent samples., Results: Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than 'all epilepsy', GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k - 2.9k variants). The other epilepsy phenotypes were insufficiently powered for MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and 'all epilepsy', and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), 'all epilepsy' (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 3.62 × 10
-7 ; 'all epilepsy': p = 2.58 × 10-3 )., Conclusion: Our study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments., Competing Interests: Declaration of competing interest O.A.A. has received speaker's honorarium from Lundbeck, Sunovion, Takeda, Janssen and is a consultant for CorTechs.ai and Precision Health AS. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board. He is also a member of the Scientific Advisory Board of Healthlytix and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. Remaining authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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