Unraveling the shared genetics of common epilepsies and general cognitive ability.

Cognition ConjFDR Conjunctional False Discovery Rate Epilepsy Gaussian causal mixture models LDSC Linkage disequilibrium score regression MiXeR Polygenic overlap

Journal

Seizure
ISSN: 1532-2688
Titre abrégé: Seizure
Pays: England
ID NLM: 9306979

Informations de publication

Date de publication:
27 Sep 2024
Historique:
received: 12 07 2024
revised: 18 09 2024
accepted: 24 09 2024
medline: 11 10 2024
pubmed: 11 10 2024
entrez: 10 10 2024
Statut: aheadofprint

Résumé

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. 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. 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 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.

Identifiants

DOI: 10.1016/j.seizure.2024.09.016 PMID: 39388989
pubmed: 39388989
pii: S1059-1311(24)00264-4
doi: 10.1016/j.seizure.2024.09.016
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

105-112

Commentaires et corrections

Type : UpdateOf

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Naz Karadag (N)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: naz.karadag@medisin.uio.no.

Espen Hagen (E)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: espen.hagen@medisin.uio.no.

Alexey A Shadrin (AA)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental disorders, University of Oslo and Oslo University Hospital, Oslo, Norway. Electronic address: alexey.shadrin@medisin.uio.no.

Dennis van der Meer (D)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway; School of Mental Health and Neuroscience, Faculty of Health, Maastricht University, Maastricht, Netherlands. Electronic address: d.van.der.meer@medisin.uio.no.

Kevin S O'Connell (KS)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: k.s.oconnell@medisin.uio.no.

Zillur Rahman (Z)

Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: zillurbmb51@gmail.com.

Gleda Kutrolli (G)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: gleda.kutrolli@medisin.uio.no.

Nadine Parker (N)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: nadine.parker@medisin.uio.no.

Shahram Bahrami (S)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: shahram.bahrami@medisin.uio.no.

Vera Fominykh (V)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway. Electronic address: vera.fominykh@medisin.uio.no.

Kjell Heuser (K)

Department of Neurology, Oslo University Hospital, Oslo, Norway. Electronic address: kheuser@ous-hf.no.

Erik Taubøll (E)

Department of Neurology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: erik.tauboll@medisin.uio.no.

Torill Ueland (T)

Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway. Electronic address: torill.ueland@psykologi.uio.no.

Nils Eiel Steen (NE)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway. Electronic address: n.e.steen@medisin.uio.no.

Srdjan Djurovic (S)

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: srdjan.djurovic@medisin.uio.no.

Anders M Dale (AM)

Department of Cognitive Science, University of California, San Diego, United States; Multimodal Imaging Laboratory, University of California, San Diego, United States; Department of Psychiatry, University of California, San Diego, United States; Department of Neurosciences, University of California, San Diego, United States. Electronic address: andersmdale@gmail.com.

Oleksandr Frei (O)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway; Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway. Electronic address: oleksandr.frei@medisin.uio.no.

Ole A Andreassen (OA)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental disorders, University of Oslo and Oslo University Hospital, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: ole.andreassen@medisin.uio.no.

Olav B Smeland (OB)

Centre for Precision Psychiatry, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: o.b.smeland@medisin.uio.no.

Classifications MeSH