Multisite, Multiancestry Genome-Wide Association Study Meta-Analysis of Functional Seizure Disorder in a Hospital Sample of 675,680 Patients
Journal
Biological Psychiatry Global Open Science
Journal Volume
6
Journal Issue
1
Start Page
Article Number 100604
ISSN
2667-1743
Date Issued
2026-01
Author(s)
Goleva, Slavina B.
Leu, Costin
Burstein, David
Venkatesh, Sanan
Birnbaum, Rebecca
Rajagopal, Veera M.
Straub, Peter
Christensen, Jakob
Bautista, Jocelyn F.
Busch, Robyn M.
Najm, Imad M.
Grove, Jakob
Børglum, Anders D.
Voloudakis, Georgios
Roussos, Panos
Smoller, Jordan
Lal, Dennis
Davis, Lea K.
Abstract
Background: Functional seizures (FS) are paroxysmal episodes that phenotypically resemble epileptic seizures but are not associated with brain epileptiform discharges; they are also known as psychogenic nonepileptic seizures. The exact etiology and pathophysiology of FS is unknown; however, trauma and stress-related disorders are known risk factors.
Methods: We used a validated algorithm applied to electronic health records to identify individuals with FS in 6 international biobanks and hospital sites. We conducted a multisite FS genome-wide association study (GWAS) meta-analysis, including 10,910 FS cases (9040 predicted European ancestry [EA] and 1870 predicted African ancestry [AA]) and 664,500 (561,150 EA and 103,350 AA) control participants.
Results: The EA meta-analysis identified significant single nucleotide polymorphism-based heritability on the liability scale of 2.21% (SE = 0.015%, p = 10-3; assumed FS prevalence = 0.14%), but no genome-wide significant loci. Nominal associations emerged from the EA GWAS within 16q23.3 (CDH13 intronic variant rs8056064, effect allele = A, z = -4.762, p = 1.92 × 10-6) and from the AA GWAS within 17q21.2 (rs34380994, effect allele = T, z = 5.28, p = 1.32 × 10-7). Significantly associated gene sets included magnesium ion transport, mitochondrial membrane complexes, and RNA polymerase II preinitiation complex assembly (Bonferroni-corrected p values = .0095, .012, and .03, respectively). MAGMA gene property analysis for tissue specificity showed significant enrichment of FS-associated genes within cerebellum-expressed genes (beta = 0.019, SE = 0.0059, p = 7.1 × 10-3).
Conclusions: To our knowledge, this is the first GWAS of FS, and our results support a genetic basis of FS. Future large-scale genetic research studies are needed to corroborate these findings and identify genetic variants associated with FS.
Subjects
Epilepsy
Functional seizures
GWAS
PNES
PTSD
Trauma
Publisher
Elsevier BV
Type
journal article