OSLO, Eastern Norway, NORWAY, 10 March 2026 — An insightful mini-review published in Genomic Psychiatry synthesizes the rapidly expanding landscape of molecular genetic research on common epilepsies, assembling evidence from genome-wide association studies, whole-exome sequencing projects, and advanced statistical modeling to illuminate the polygenic architecture that underpins these heterogeneous neurological disorders. The synthesis, led by Dr. Olav B. Smeland of the Centre for Precision Psychiatry at Oslo University Hospital and the University of Oslo, draws a detailed portrait of a genetic landscape far more intricate than early twin studies ever suggested.
Epilepsy is not one disease. It is a constellation of seizure disorders that affects approximately 50 million people globally and carries increased mortality, psychiatric comorbidity, and, for roughly one-third of patients, resistance to existing medications. What determines who develops epilepsy, which subtype emerges, and who responds to treatment? Those questions have driven genetic research along two parallel tracks for decades. One track has yielded dramatic results: studies of severe monogenic epilepsies, such as developmental and epileptic encephalopathies, have identified over a thousand implicated genes. The other track, focused on common epilepsies including genetic generalized epilepsy and focal epilepsy, has moved more slowly, hindered by the sheer complexity of polygenic inheritance.
Twin Studies Set the Stage
The review traces the evidentiary thread back to twin studies of the 1930s, which first demonstrated higher concordance rates for epilepsy among monozygotic twins compared with dizygotic twins. The largest such study, encompassing 47,626 twin pairs, found concordance of 28% in monozygotic twins versus 7% in dizygotic twins. But the numbers diverge further when epilepsy subtypes are examined separately. For genetic generalized epilepsy, monozygotic concordance reached 77% and dizygotic concordance was 35%; for focal epilepsy, those figures dropped to 40% and 3%, respectively. How can two broad categories of the same disorder exhibit such profoundly different inheritance patterns? That question animates much of what follows in the review.
Modern molecular methods have quantified this heritability in a different currency. The SNP-heritability, the fraction of phenotypic variation attributable to common genetic variants, is estimated to be approximately three times larger for genetic generalized epilepsy than for focal epilepsy. Specific subtypes such as juvenile myoclonic epilepsy and childhood absence epilepsy show even higher heritability estimates, underscoring that diagnostic precision matters enormously in genetic research.
Rare Variants Tell a Different but Convergent Story
The review describes how rare genetic variants, those with a minor allele frequency below 1%, also contribute to epilepsy risk, although they are present in only a minority of cases. A study involving 13,420 epilepsy cases demonstrated increased copy number variant burden across all common epilepsy types compared with controls, with genetic generalized epilepsy showing the highest burden. Recurrent deletions at the 15q13.3 locus emerged as the strongest risk factor for genetic generalized epilepsy, with an odds ratio of 36.04. Can a single chromosomal deletion carry that much weight in a condition shaped by thousands of variants? The answer appears to be yes, but only for a small fraction of patients.
Whole-exome sequencing studies have identified protein-truncating ultrarare variants in genes encoding components of the GATOR1 complex, a negative regulator of the mTORC1 pathway, as robust contributors to non-acquired focal epilepsy risk. What makes these findings especially compelling, as the review authors note, is the convergence between rare and common variant signals. Genes like DEPDC5, NPRL3, SCN1A, and SCN8A appear in both rare variant analyses and common variant association studies, pointing toward shared biological pathways involving ion channel function, synaptic excitability, and excitatory-inhibitory balance.
The Common Variant Landscape Expands
The largest genome-wide association study of common epilepsies to date, conducted by the International League Against Epilepsy with 29,944 cases and 52,538 controls, identified 26 genome-wide significant loci. The distribution was strikingly uneven. Twenty-two loci were associated with genetic generalized epilepsy from only 7,407 cases, while focal epilepsy, despite more than twice as many cases at 16,384, yielded no genome-wide significant associations. This asymmetry is not merely a matter of sample size, the review authors argue, but reflects fundamental differences in genetic architecture between subtypes.
"The genetic architecture of generalized epilepsies offers an unusually favorable ratio of heritability to polygenicity," said Dr. Olav B. Smeland, corresponding author and researcher at the Centre for Precision Psychiatry, Oslo University Hospital and University of Oslo. "Our power projections suggest that a modestly larger GWAS for genetic generalized epilepsy could capture approximately 50% of its common genetic variance, making it remarkably cost-efficient compared with other complex brain disorders."
Among the 29 potential causal genes prioritized from those 26 loci, ten are established monogenic epilepsy genes, including ion channel subunits such as SCN8A, SCN1A, CACNA1I, and KCNN2, along with neurotransmitter receptor components GABRA2 and GRIK1. This genetic convergence between monogenic and polygenic forms of epilepsy is perhaps the review's most striking integrative insight. It suggests that the same biological highways carry traffic from both directions, from rare high-impact mutations and from the cumulative pressure of thousands of common variants.
Where Epilepsy Meets Psychiatry at the Genomic Level
The review devotes substantial attention to genetic pleiotropy, the phenomenon whereby genetic variants influence more than one phenotype. The genome-wide genetic correlation between focal epilepsy and genetic generalized epilepsy is 0.61, indicating that many common variants jointly increase risk for both. But the overlaps extend far beyond epilepsy subtypes. Both focal and generalized epilepsies show moderate negative genetic correlations with cognitive ability, consistent with the well-documented cognitive impairment seen in epilepsy patients.
Using the bivariate MiXeR model, the review authors demonstrate that most variants associated with genetic generalized epilepsy are also associated with major psychiatric disorders, including schizophrenia, major depression, bipolar disorder, and anxiety. This overlap is substantial even when genome-wide genetic correlations are modest, because many shared variants exert effects in mixed directions. Does a variant that raises epilepsy risk also raise depression risk? Sometimes yes, sometimes in the opposite direction, which masks the overlap in traditional correlation analyses.
"The extensive genetic overlap between epilepsy and psychiatric disorders provides a molecular explanation for what clinicians have long observed at the bedside," said Naz Karadag, first author and researcher at the Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo. "Understanding these shared genetic foundations may eventually help identify epilepsy patients at elevated risk for psychiatric comorbidities."
The review also highlights a less intuitive finding: approximately 30% to 40% of the common variants contributing to epilepsy risk overlap with variants influencing cortical thickness and cortical surface area, despite the absence of significant genome-wide genetic correlations between these phenotypes. What does it mean when two traits share genetic variants but not correlated effects? It means the relationship is more tangled than simple directional associations can capture.
Clinical Translation Remains a Horizon, Not a Destination
On the clinical front, the review is carefully measured. Genetic testing is currently established for severe early-onset or syndromic epilepsies, where identifying a pathogenic variant may guide treatment. But for common epilepsies, with their complex inheritance and the fact that only a minority of cases harbor rare pathogenic variants of large effect, routine genetic testing remains premature.
Polygenic risk scores offer a different angle. The lifetime risk of epilepsy increases by a hazard ratio of 1.73 per standard deviation increase in a genetic generalized epilepsy polygenic risk score, a figure comparable to polygenic risk prediction in cardiology. Yet the discriminative performance remains insufficient for population screening. And a critical equity gap persists: over 92% of cases in the largest epilepsy GWAS are of European ancestry, severely limiting the generalizability of risk scores across populations.
"Polygenic risk scores for epilepsy show promise in specific clinical contexts, such as risk stratification after a first unprovoked seizure," said Dr. Smeland. "But we must be cautious. Current scores should not be used for routine clinical decision-making, and broadening ancestral diversity in our study populations is essential before any implementation can be considered equitable."
The Cost-Efficiency Argument for Larger Studies
One of the review's most compelling analytical contributions involves GWAS power projections generated using the MiXeR framework. At current sample sizes for genetic generalized epilepsy (effective N of approximately 23,000), only about 1.5% of SNP-heritability is explained by genome-wide significant variants. By comparison, a stroke GWAS with an effective sample size more than ten times larger (278,000) explains a similar fraction of heritability at 2.0%. If genetic generalized epilepsy GWAS were scaled to comparable sample sizes, approximately 50% of common genetic variance could be captured. The investment required is smaller than for most other complex brain disorders, and the yield would be disproportionately large.
Could the epilepsy genetics community be sitting on one of the most efficient opportunities in complex disease genomics? The power projections suggest exactly that.
Critical Gaps That Demand Attention
The review does not shy away from limitations. Existing datasets are predominantly European and drawn from a narrow range of sources. The role of somatic mosaicism in common epilepsies remains largely unexplored. The statistical power for focal epilepsy GWAS is currently insufficient for reliable MiXeR analysis, leaving a significant portion of the epilepsy landscape unmapped. And the phenotypic categories used in large-scale genetic studies, broad groupings like focal epilepsy or genetic generalized epilepsy, may not capture the clinical granularity needed to detect subtype-specific genetic signals.
"We are still at an early stage of genetic discovery for common epilepsies," said Julian Fuhrer, co-author and researcher at the Centre for Precision Psychiatry, Oslo University Hospital and University of Oslo, who generated all data analyses and figures for the review. "The genetic signal is there, the tools are improving, and the returns on investment in larger, more diverse samples are clear. What we need now is the coordinated effort to make it happen."
A Multimodal Future
Looking forward, the review envisions a future in which genetics is integrated with other data modalities, including clinical and cognitive variables, other omics data, electronic health records, neuroimaging, electrophysiology, and sensing device phenotypes, to construct genuinely multimodal prediction models. Large biobanks with longitudinal data, such as the UK Biobank and the All of Us Research program, will be essential platforms. Rapidly advancing artificial intelligence and machine-learning algorithms may provide the computational means to integrate these diverse data streams effectively.
The synthesis by Dr. Smeland and colleagues, including co-authors Dr. Kjell Heuser of the Department of Neurology at Oslo University Hospital and Professor Ole A. Andreassen of the Centre for Precision Psychiatry and the KG Jebsen Centre for Neurodevelopmental Disorders at the University of Oslo, represents a clear-eyed inventory of what the field knows, what it suspects, and what it still cannot answer. Will the next generation of epilepsy GWAS deliver the clinical translation that decades of genetic research have promised? The architecture of common epilepsies, with its favorable heritability-to-polygenicity ratio, suggests the answer may be closer than many expect.
The peer-reviewed mini-review in Genomic Psychiatry titled “The genetics of common epilepsies,” is freely available via Open Access, starting on 10 March 2026 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp026y.0027 .
The full reference for citation purposes is: Karadag N, Fuhrer J, Heuser K, Andreassen OA, and Smeland OB. The genetics of common epilepsies. Genomic Psychiatry 2026. DOI: https://doi.org/10.61373/gp026y.0027 . Epub 2026 Mar 10.
About Genomic Psychiatry: Genomic Psychiatry: Advancing Science from Genes to Society (ISSN: 2997-2388, online and 2997-254X, print) represents a paradigm shift in genetics journals by interweaving advances in genomics and genetics with progress in all other areas of contemporary psychiatry. Genomic Psychiatry publishes peer-reviewed medical research articles of the highest quality from any area within the continuum that goes from genes and molecules to neuroscience, clinical psychiatry, and public health.
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Genomic Psychiatry
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The genetics of common epilepsies
10-Mar-2026
OAA has received speaker’s honoraria from Lundbeck, Sunovion, Takeda, and Janssen and is a consultant for Cortechs.ai. The other authors declare no competing interests.