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

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.