Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available 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), and as well as specific subtypes. We functionally annotated the identified loci using a variety of 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 analysis. We show extensive genetic overlap between COG and epilepsies with significant 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 = 1.0 × 10 -14; ′all epilepsy′: p = 5.6 × 10 -3). Significance: Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity–targeted epilepsy treatments.

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.

All GWAS investigated in the present study were approved by the local ethics committees, and informed consent was obtained from all participants. We thank the ILAE consortium and the FinnGen biobank for access to data, and the many participants who provided DNA samples. This work was performed on Services for sensitive data (TSD), University of Oslo, Norway, with resources provided by UNINETT Sigma2 – the National Infrastructure for High Performance Computing and Data Storage in Norway. The project is funded by ERA–NET–NEURON (Application no: ES609126, Project NMDAR–PSY) which is funded by participating Research Councils across Europe. The work was supported by the Research Council of Norway (262656, 249711, 248980, 248778, 226971, 223273, 300309, 324252, 324499, 326813 and 334920), South–East Norway Regional Health Authority (2016 –064, 2022–073 and 2022–087), KG Jebsen Stiftelsen (SKGJ–MED–008), European Union′s Horizon 2020 Research and Innovation Programme (847776, CoMorMent; 964874, RealMent; and 801133, Marie Sklodowska–Curie Actions) and EAA grant (EEA–RO–NO–2018–0573). K.S.O., G.K. and A.M.D. were supported by NIH (K.S.O: 5R01MH12483902; G.K.: R01MH12372401; A.M.D.: U24DA041123, R01AG076838, U24DA055330, and OT2 HL161847). S.B. was supported by Norwegian Health Association (22731).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

GWAS summary statistics used in this study are publicly available and can be accessed through the original publications. Each sample was collected with the participants written informed consent and with approval by local institutional review boards. The use of summary statistics for genetic analysis was evaluated by The Norwegian Institutional Review Board: Regional Committees for Medical and Health Research Ethics (REC) South-East Norway and found that no additional ethical approval was required because no individual data were used.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes