Epilepsy and bipolar disorder (BD) exhibit considerable biochemical and genetic overlap. This study revealed a significant genetic correlation between type 1 BD and epilepsy, indicating a significant causal effect of epilepsy on BD. In addition, they identified shared genetic variants important for neuronal function and their expression in different areas of the brain.
Epilepsy and bipolar disorder (BD), especially the mania form associated with BD, are conditions that share biological and genetic characteristics, according to growing scientific evidence. Both present alterations in the concentration of calcium ions within cells ([Ca2+]), a phenomenon consistently observed in biochemical studies.
This link is further reinforced by the fact that some medications used to treat epilepsy, called antiepileptics, are also effective in controlling mood in patients with BD, suggesting a common biological basis between the two disorders.
This raises the hypothesis that mood changes, such as mania, may be related to the mechanisms that lead to seizures.
Researchers from the Chinese Academy of Sciences conducted an in-depth study using data from genome-wide association studies (GWAS), which investigate DNA variations in large populations to identify genes associated with diseases.
The study analyzed 26,352 cases of epilepsy and 774,517 individuals without epilepsy (controls), as well as 25,060 cases of bipolar I disorder (BD-I), which is characterized by episodes of severe mania, and 307,499 controls.
The analysis revealed a significant positive genetic correlation between BD-I and epilepsy. In simple terms, this means that there are shared genes that may contribute to the development of both conditions.
Venn plot showing the number of specific causal variants shared between BD-I and epilepsy. Source: Jin-Hua Huo, and Ming Li
In addition, the data suggest that epilepsy may have a causal effect on the development of BD-I, indicating that people with epilepsy may be at increased risk of developing BD-I.
Another interesting aspect of the study was the identification of specific genetic variants. Using a technique called MiXeR. MiXeR is an advanced statistical approach used in genetic studies to analyze and quantify the overlap of multiple genes between different conditions or traits.
In simple terms, it allows the identification of the estimated number of genetic variants that simultaneously influence two or more conditions, even when these conditions do not appear to have an obvious or direct correlation in clinical outcomes.
In this study, scientists found approximately 7,800 genetic variants associated with BD-I, another 3,000 associated with epilepsy, and 1,300 variants shared between both conditions.
In addition, six specific regions of the genome (called genomic loci) were significantly associated with BD-I and epilepsy. Of these, four regions showed similar genetic effects for both diseases, while two showed opposite effects. This suggests that some variants may influence both conditions in a similar way, while others may act divergently.
Among the genes analyzed, the SP4 gene received particular attention. A specific variant of this gene, identified as rs9639379, was associated with both the risk of BD-I and epilepsy.
The SP4 gene is involved in regulating the transcription of genes related to neuronal energy metabolism, which is important for both normal brain function and the response to conditions such as epilepsy and BD.
Studies indicate that the stability of the SP4 protein can be influenced by neuronal activity, and lithium, a drug widely used to treat BD, has been shown to stabilize levels of this protein. This suggests that SP4 may play an important role in the effectiveness of mood stabilizers.
Although the direct link between SP4 and epilepsy is not yet fully understood, its influence on neuronal metabolism provides a clue as to how it may be involved in epileptic seizures.
The study also found that five of the six genomic loci shared between BD-I and epilepsy showed associations with gene expression in cerebral cortex tissues or in specific cell types. This reinforces the idea that alterations in specific genes can impact brain regions related to both conditions.
Despite the significant advances, the study has limitations. It was conducted with populations of European descent, which may limit the applicability of the results to other populations. In addition, the data used did not include specific information on the sex of the participants, preventing gender-based analyses that could bring more nuance to the findings.
In summary, this study reinforces the biological and genetic connection between epilepsy and bipolar disorder, revealing a substantial overlap in the mechanisms underlying the two conditions.
The identification of shared genetic variants, such as rs9639379 in the SP4 gene, offers new clues to understand the relationship between these diseases. In addition, the results highlight the potential of mood-stabilizing medications, which are already effective in both conditions, to explore new therapeutic avenues.
Future research should focus on better understanding shared genetic and neurobiological mechanisms, expanding analyses to diverse populations, and exploring the influence of specific factors such as gender.
READ MORE:
Rethinking the connection between bipolar disorder and epilepsy from genetic perspectives
Jin-Hua Huo, and Ming Li
Genomic Psychiatry, Page Range: 1 – 2, Brief Report, Sep 30, 2024
Abstract:
Epilepsy and bipolar disorder (BD) exhibit considerable biochemical and genetic overlap. Our study unveiled a significant genetic correlation (rg = 0.154, P = 9.24 × 10–6) between BD-I and epilepsy, indicating a meaningful causal effect of epilepsy on BD-I (P = 0.0079, bxy = 0.1721, SE = 0.0648). Additionally, we identified 1.3k shared genetic variants and 6 significant loci, demonstrating substantial polygenic overlap. Notably, the rs9639379 variant within the SP4 gene exhibited strong associations with both BD-I and epilepsy, implicating SP4 in the etiology of both disorders.
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