Multisite, Multiancestry Genome-Wide Association Study Meta-Analysis of Functional Seizure Disorder in a Hospital Sample of 675,680 Patients

Authors

• Slavina B Goleva
• Costin Leu
• Yen-Chen Anne Feng
• David Burstein
• Sanan Venkatesh
• Rebecca Birnbaum
• Veera M Rajagopal
• Peter Straub
• Jakob Christensen
• Jocelyn F Bautista
• Robyn M Busch
• Imad M Najm
• Jakob Grove
• Anders D Børglum
• Georgios Voloudakis
• Panos Roussos
• Jordan Smoller
• Dennis Lal
• Lea K Davis

Language

English

Publication Date

1-1-2026

Journal

Biological Psychiatry Global Open Science

DOI

10.1016/j.bpsgos.2025.100604

PMID

41234274

PMCID

PMC12607027

PubMedCentral® Posted Date

9-2-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Epilepsy, Functional seizures, GWAS, PTSD, PNES, Trauma

Published Open-Access

yes

Recommended Citation

Goleva, Slavina B; Leu, Costin; Anne Feng, Yen-Chen; et al., "Multisite, Multiancestry Genome-Wide Association Study Meta-Analysis of Functional Seizure Disorder in a Hospital Sample of 675,680 Patients" (2026). Faculty, Staff and Student Publications. 3776.
https://digitalcommons.library.tmc.edu/uthmed_docs/3776