Using Genetics to Shed Light on the Scientific Gray Zone of Functional Seizures

Functional neurological disorders, including functional seizures (FSs), have long existed in a scientific gray zone. These disorders of exclusion are defined by their lack of a medically identifiable cause, and therefore, patients with the conditions may face stigma and skepticism. From ancient Mesopotamian beliefs about divine punishment to the Greek notion of a “wandering womb” to early psychoanalytic theories of unconscious conflict, functional symptoms such as these have seemingly always invited speculation about their origins (1). Although the various interpretations highlight society’s enduring curiosity about the nature of these conditions, historically they have placed the burden on the patient, casting functional symptoms as evidence of a personal failing or moral weakness. In doing so, historical explanatory models have frequently reinforced stigma even as they sought to provide meaning.

Genetic research has the potential to ground these conditions in biological mechanisms instead. These studies provide scientific insights that may ultimately improve diagnosis and treatment of FS for patients; additionally, the findings can serve as a powerful counter message to the false dichotomy between so-called real and psychogenic conditions. The recent study of Goleva et al. (2) in Biological Psychiatry: Global Open Science marks a critical first step toward understanding the genetic architecture of FS. FS affects as many as 2 in 5 patients in epilepsy monitoring units and has an estimated population prevalence of 0.11% to 0.14% (3). Leveraging a validated algorithm to identify 10,910 cases, the authors conducted the first genome-wide association study (GWAS) of FS in individuals genetically similar to the 1000 Genomes Project European (EA) and African ancestry reference populations (2). Although no loci reached genome-wide significance, FS demonstrated significant single nucleotide polymorphism–based heritability (2.21%, SE = 0.015%) in EA individuals, suggesting a polygenic architecture underlying the condition. The lack of genome-wide significant findings mirrors that of many early GWASs of complex psychiatric and behavioral traits, for which large samples and consortia efforts have been needed to identify replicable loci. It is likely that FS must similarly reach a sample size inflection point, at which time GWASs will begin to yield associations.

Despite a lack of genome-wide significant findings, Goleva et al. (2) highlight biological mechanisms that may contribute to FS. Gene-set analyses indicated that genes involved in magnesium ion transport were enriched for associations with FS, consistent with previous research that has linked magnesium deficiency to increased cortical excitability and seizure susceptibility (4). Thus, magnesium may play a role in the pathophysiology of FS, and its involvement in both functional and epileptic seizures points to a potential source of biological overlap. In addition to the identification of significant gene sets, expression of FS-associated genes was enriched in the cerebellum and cerebellar hemisphere. Long recognized for having roles in motor coordination, there is a growing understanding that the cerebellum also contributes to sensory integration, and cerebellar involvement has been implicated in both chronic pain and migraine (5,6). Together, these signals for FS-associated genes offer compelling directions for future research into the etiology of FS.

Given the potential roles of trauma and stressors in the etiology of FS (7), Goleva et al. also examined whether global genetic correlations between FS and posttraumatic stress disorder (PTSD) could be identified (2). Although the point estimate of the genetic correlation was positive (r_g = 0.092), large standard errors reflected the underpowered nature of this analysis and precluded drawing firm conclusions about the presence or absence of genetic overlap. However, the inclusion of this analysis raises a broader point about the interpretation of genetic associations between FS and psychiatric traits such as PTSD. Particularly considering the long history of stigmatization of functional conditions, if the genetic correlation with PTSD had been positive and significant rather than small and null, what conclusions should that lead us to about the nature of FS? Genetic overlap with psychiatric traits should not be misinterpreted as a mark against the legitimacy of FS. Rather than reflecting a vindication of the longstanding real versus psychogenic medical divide, findings of genetic overlap between medical and psychiatric traits are increasingly being identified (8), and this overlap highlights the often-rudimentary distinctions that medical science has made between mental and physical health. As genetic research into FS grows, the underlying biology is likely to increasingly produce the realization that despite historical labels as psychogenic, these conditions are no less real than other seizure and neurological disorders that have been subject to less controversy.

The study of Goleva et al. (2) reflects a shift toward deeper scientific engagement with functional and somatoform disorders. These conditions are more common than was previously believed, and they often have disabling effects on patients. Furthermore, the process of receiving a diagnosis of FS is often a long one, with an average diagnostic delay of more than 8 years (9). For those who do receive a diagnosis, there are currently no medications recommended for its treatment. Despite the considerable patient burden and the clear need to improve patient outcomes, functional conditions such as FS remain underrepresented in genetic studies that could help identify their underlying mechanisms. Expanding genetic research into these conditions may improve their diagnosis and classification, inform the development of novel therapeutics, and help reduce the stigma that has long surrounded them. A better understanding of the genetic architecture of FS may one day help distinguish them from other seizure disorders earlier in the diagnostic process, thereby preventing patients from waiting many years to receive an appropriate diagnostic label. Although the clinical utility of genetic research on FS seems distant currently, it is important to keep the goal of improving patient care in view. Studies such as the one by Goleva et al. (2) help lay the foundation for a more comprehensive and evidence-based approach to conditions that have, for too long, existed at the margins of psychiatry and neurology.

There are several directions for future research to build on the work of Goleva et al. As is evident from their study’s lack of genome-wide significant findings, larger sample sizes will be needed to detect associated loci, and this will require collaborative efforts that prioritize the inclusion of individuals from multiple genetic ancestry groups. Additionally, combining genetic data with other sources of biological and clinical information (e.g., neuroimaging and epigenetics) may help clarify the complex and dynamic pathways that link stress, brain structure and function, and FS. As with the need to incorporate multiple data types, research on FS will also require moving beyond traditional silos that have separated mental and physical health. Investigating the genetic overlap of FS with psychiatric traits and physical health conditions such as cerebrovascular disease may identify shared genetic etiologies and therapeutic targets for addressing common comorbidities. Finally, research that incorporates patient perspectives can help ensure that scientific discoveries better translate into meaningful improvements in patient quality of life and do not unintentionally increase stigma. Although additional work in this area is clearly needed, the foundational research of Goleva et al. (2) brings us closer to a more biologically informed understanding of FS.