Polygenic risk scores as a marker for epilepsy risk across lifetime and after unspecified seizure events.

Autor:	Heyne HO; Hasso Plattner Institute for Digital Engineering, University of Potsdam, Germany.; Hasso Plattner Institute, Mount Sinai School of Medicine, NY, US.; Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.; Program for Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pajuste FD; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia., Wanner J; Hasso Plattner Institute for Digital Engineering, University of Potsdam, Germany.; Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland., Onwuchekwa JID; Hasso Plattner Institute for Digital Engineering, University of Potsdam, Germany.; Faculty of Life Sciences, University of Siegen, Germany., Mägi R; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia., Palotie A; Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.; Program for Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kälviainen R; Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital, Member of ERN EpiCARE, Kuopio, Finland.; Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland., Daly MJ; Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.; Program for Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Nov 27. Date of Electronic Publication: 2023 Nov 27.
DOI:	10.1101/2023.11.27.23297542
Abstrakt:	A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence epilepsy risk in detailed longitudinal electronic health records (EHRs) of > 360k Finns spanning up to 50 years of individuals' lifetimes. Individuals with a high genetic generalized epilepsy PRS (PRS GGE ) in FinnGen had an increased risk for genetic generalized epilepsy (GGE) (hazard ratio [HR] 1.55 per PRS GGE standard deviation [SD]) across their lifetime and after unspecified seizure events. Effect sizes of epilepsy PRSs were comparable to effect sizes in clinically curated data supporting our EHR-derived epilepsy diagnoses. Within 10 years after an unspecified seizure, the GGE rate was 37% when PRS GGE > 2 SD compared to 5.6% when PRS GGE < -2 SD. The effect of PRS GGE was even larger on GGE subtypes of idiopathic generalized epilepsy (IGE) (HR 2.1 per SD PRS GGE ). We further report significantly larger effects of PRS GGE on epilepsy in females and in younger age groups. Analogously, we found significant but more modest focal epilepsy PRS burden associated with non-acquired focal epilepsy (NAFE). We found PRS GGE specifically associated with GGE in comparison with >2000 independent diseases while PRS NAFE was also associated with other diseases than NAFE such as back pain. Here, we show that epilepsy specific PRSs have good discriminative ability after a first seizure event i.e. in circumstances where the prior probability of epilepsy is high outlining a potential to serve as biomarkers for an epilepsy diagnosis. Competing Interests: Competing interests M.J.D. is a founder of Maze Therapeutics.
Databáze:	MEDLINE
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