Submitted:
04 December 2024
Posted:
05 December 2024
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Abstract
Background: Sleep and epilepsy have been reported to have a possible interaction. This study intended to assess the causal relationship between sleep traits and epilepsy risk through a two-sample Mendelian randomization (MR) study. Methods: Exposure- [sleep traits: getting up in morning, sleeplessness/insomnia, sleep duration, nap during day, morning/evening person (chronotype), daytime dozing/sleeping (narcolepsy).] and outcome- [Europeans: epilepsy, focal epilepsy, generalized epilepsy; East Asians: epilepsy] related single-nucleotide polymorphisms (SNPs) from publicly available genome-wide association studies (GWAS) databases were used as instrumental variables for analysis. The main analyses used inverse variance weighted (IVW) to derive causality estimates, which were expressed as odds ratio (OR) and 95% confidence interval (CI). Sensitivity analyses were performed to assess the reliability of the results. Results: For Europeans, genetically predicted getting up in morning decreased the risk of epilepsy (OR=0.354, 95%CI: 0.212-0.589) and generalized epilepsy (OR=0.256, 95%CI: 0.101-0.651), whereas genetically predicted evening person (chronotype) increased the risk of epilepsy (OR=1.371, 95%CI: 1.082-1.739) and generalized epilepsy (OR=1.618, 95%CI: 1.061-2.467). No significant associations were found between genetically predicted sleeplessness/insomnia, sleep duration, nap during day, and daytime dozing/sleeping (narcolepsy) and the risk of epilepsy, focal epilepsy, and generalized epilepsy in Europeans. For East Asians, only genetically predicted sleeplessness/insomnia was found to increase the risk of epilepsy (OR=1.381, 95%CI: 1.039-1.837). Conclusion: There was a causal relationship between getting up in morning and evening person (chronotype) and epilepsy risk in Europeans, and between sleeplessness/insomnia and epilepsy in East Asians.
Keywords:
sleep traits
; epilepsy
; causal link
; Mendelian randomization
; populations
Introduction
Epilepsy is one of the most common serious central nervous system disorders, affecting more than 70 million people worldwide [1]. Epilepsy is characterized by sustained easily occurring spontaneous seizures with neurobiological, cognitive and psychosocial consequences [1]. Although antiepileptic drugs can suppress up to two-thirds of seizures, they do not change the long-term prognosis and patients often suffer adverse effects from the drugs [1,2]. Identifying modifiable risk factors related to epilepsy is critical to preventing the development of epilepsy and reducing the burden of disease.
Sleep is an important part of human health, and circadian rhythm disruption can increase the risk of several diseases, including the nervous system [3,4]. There is a complex bidirectional relationship between sleep and epilepsy [5], with insomnia rates ranging from 28.9% to 74.4% and significantly worse sleep quality in patients with epilepsy [6,7]. Circadian rhythms may influence neurological function by regulating blood-brain barrier integrity [8] and may also be involved in the development of epilepsy by modulating the mammalian target of rapamycin (mTOR) pathway [9,10]. Moreover, the types of seizures are also rhythmical, which may be related to the state of alertness and circadian changes in the balance of excitability and inhibition [5]. Chronotype is a simple indicator of an individual’s biological clock, and people with generalized epilepsy more often show an evening person preference (preferring to go to bed late and get up late) [11,12]. Chronotype preference may also influence blood drug concentration and efficacy by influencing the duration of antiepileptic drug administration [5]. Several studies have attempted to regulate circadian rhythms through melatonin intervention to improve the prognosis of patients with epilepsy, but no definitive efficacy has been obtained [13]. However, the causal associations of the effects of different sleep traits on epilepsy risk remain unclear because traditional epidemiological studies are susceptible to confounding factors and causal inversion.
Mendelian randomization (MR) uses genetic variation as an instrumental variable to explore the causal association between exposure and disease [14]. In contrast to traditional observational epidemiologic studies, MR results are less susceptible to bias caused by confounders and reverse causation. Thus, this study intended to assess the causal relationship between sleep traits and epilepsy risk through a two-sample MR study.
Methods
Data Source and Study Design
This two-sample MR analysis explored the causal association between sleep traits and epilepsy risk using genetic variant data from European and East Asian populations, respectively. These genetic variant data were derived from the MRC-IEU open GWAS project (https://gwas.mrcieu.ac.uk/datasets/), which is a complete genome-wide association study (GWAS) summary dataset, and the relevant genetic variant data can be downloaded as open-source files [15]. MR studies use genetic variants, single-nucleotide polymorphisms (SNPs), associated with exposure and outcome as instrumental variables for analysis. SNPs used as instrumental variables are required to meet the three basic assumptions of MR: (1) Relevance assumption, SNPs were strongly associated with exposure; (2) Independence assumption, SNPs were not related to confounders of the relationship between exposure and outcome; (3) Exclusion restriction assumption, SNPs affect outcome variables only by affecting exposure variables (Figure 1). All ethical approvals and informed consent were obtained from the original GWAS. This study was based on a secondary analysis of publicly available data and was exempt from additional ethical approval.
Genetic Instrumental Variable
The exposure variables of this study were sleep traits, including getting up in morning, sleep apnoea, sleeplessness/insomnia, sleep duration, sleep duration (undersleepers), sleep duration (oversleepers), nap during day, morning/evening person (chronotype), and daytime dozing/sleeping (narcolepsy). Detailed descriptions of each sleep traits are provided in biobank’s touchscreen questionnaire (https://biobank.ndph.ox.ac.uk/showcase/refer.cgi?id=113241). For Europeans, SNPs related to getting up in morning were obtained from 336,501 Europeans, SNPs related to sleep apnoea from 463,010 Europeans (2,320 cases and 460,690 controls), SNPs related to sleeplessness/insomnia from 462,341 Europeans, and SNPs related to sleep duration from 460,099 Europeans, these SNPs were obtained from the MRC-IEU database. SNPs associated with sleep duration (undersleepers) and sleep duration (oversleepers) were derived from a GWAS [16], with sleep duration (undersleepers)-related SNPs from 110,188 Europeans (28,980 cases and 81,208 controls) and sleep duration (oversleepers)-related SNPs from 91,306 Europeans (10,102 cases and 81,204 controls). SNPs related to nap during day, morning/evening person (chronotype), and daytime dozing/sleeping (narcolepsy) were also obtained from a GWAS [17], with nap during day-related SNPs from 462,400 Europeans, morning/evening person (chronotype)-related SNPs from 413,343 Europeans, and daytime dozing/sleeping (narcolepsy)-related SNPs from 406,913 Europeans.
For East Asians, SNPs associated with sleep apnoea from a GWAS [18] containing SNPs from 178,337 East Asians (473 cases and 177,864 controls). SNPs related to getting up in morning were derived from 2,640 East Asians, SNPs related to sleeplessness/insomnia from 2,654 East Asians, SNPs related to sleep duration from 2,631 East Asians, SNPs related to nap during day from 2,606 East Asians, SNPs related to morning/evening person (chronotype) from 2,343 East Asians, and SNPs related to daytime dozing/sleeping (narcolepsy) from 2,582 East Asians, these SNPs were derived from the MRC-IEU database.
The outcome variable of this study was epilepsy. For Europeans, outcomes included epilepsy, focal epilepsy, and generalized epilepsy. SNPs associated with epilepsy were derived from 182,367 Europeans (6,260 cases and 176,107 controls), SNPs associated with focal epilepsy from 213,461 Europeans (929 cases and 212,532 controls), and SNPs associated with generalized epilepsy from 214,313 Europeans (1,781 cases and 212,532 controls). These SNPs were obtained from the MRC-IEU database, with the original source being the FinnGEN database (https://r7.finngen.fi/). For East Asians, the only outcome was epilepsy, and SNP related to epilepsy were obtained from 212,453 East Asians (2,143 cases and 210,310 controls) in the MRC-IEU database. The sources of SNPs associated with exposure and outcome were summarized in Supplement Table 1.
Selection of Instrumental Variables
To ensure that instrumental variables met the requirements for MR analysis, a series of quality control processes were performed to screen SNPs related to exposure and outcome. SNPs should be strongly related to exposure at the genome-wide statistical significance threshold (P < 5 × 10-8 or P < 5 × 10-6). Then, SNPs with linkage disequilibrium (LD) (r2=0.001, clump distance=10,000 kb) were excluded to obtain independent SNPs. Third, palindromic SNPs with intermediate allele frequencies were also excluded. Finally, the screened exposure-related SNPs were harmonized with the outcome-related SNPs through the “harmonise_data” function in the TwoSampleMR package, so that the exposure and the outcome had the same allele.
Statistical Analysis
Multiple MR methods were utilized to investigate the causal relationship between sleep traits and epilepsy risk, including inverse-variance weighted (IVW), weighted median, weighted mode, MR-PRESSO, and Radial MR. The IVW method was reported to be more powerful than the other methods [19], so the results of IVW were used as the main results and the other MR methods were used as supplements. The results of IVW include the results of multiplicative random effects and fixed effects. If there is heterogeneity among SNPs, the results of IVW are based on multiplicative random effects, otherwise the results of IVW are based on fixed effects.
Several tests or sensitivity analyses were performed to assess the reliability of the results of the MR analysis. The strength of SNPs was tested using the F-statistic and variance explained (R2), and SNPs with an F-statistic less than 10 were considered weak instrument variables. The calculations of F-statistic [20] and R2 [21] were based on formulas from previous studies. The presence of horizontal pleiotropy would violate the independence assumption and exclusion restriction assumption in MR study. Horizontal pleiotropy is the association of a genetic variant with multiple risk factors on different causal pathways. Horizontal pleiotropy was assessed by the MR-Egger intercept test, and a P-value of the test less than 0.05 was considered to have horizontal pleiotropy. Heterogeneity was measured by Cochran’s Q statistic from MR-Egger and IVW analyses, and a P-value for the Q statistic of less than 0.05 was considered to have heterogeneity. The MR Steiger directionality test was utilized to evaluate whether the causal association between the exposure to the outcome was in the right direction. In addition, the leave-one-out analysis was performed to assess whether the causal relationship was caused by an individual SNP. All MR analyses were performed using the “TwoSampleMR” package in R version 4.1.3 software (Institute for Statistics and Mathematics, Vienna, Austria). A P-value < 0.05 was considered statistically significant.
Results
Characteristics of Instrumental Variables
The screening process and strength tests for SNPs associated with sleep traits and epilepsy were listed in Table 1 (Europeans) and Supplement Table 2 (East Asians). Among the SNPs included in the MR analysis, the number of SNPs associated with sleep traits in Europeans ranged from 31 to 150, whereas the number of SNPs related to sleep traits in East Asians ranged from 2 to 7. The strength test showed that the F-statistics of these SNPs ranged from 22 to 40 (>10), indicating that there were no weak instrumental variables for these SNPs. The results of the horizontal pleiotropy and heterogeneity tests were presented in Table 2. The horizontal pleiotropy test demonstrated that there was no horizontal pleiotropy among these SNPs (P>0.05). For Europeans, there was heterogeneity in SNPs between morning/evening person (chronotype) and epilepsy, between morning/evening person (chronotype) and daytime dozing/sleeping (narcolepsy) and focal epilepsy, and between nap during day and generalized epilepsy (P<0.05). For East Asians, there was no heterogeneity among these SNPs (P>0.05). Moreover, the MR Steiger directionality test demonstrated that the direction of the relationship between sleep traits and epilepsy risk was “TURE” in both Europeans and East Asians, suggesting a causal relationship.
Causal Relationship Between Sleep Traits and Epilepsy Risk
The IVW results of the relationship between sleep traits and epilepsy risk in Europeans and East Asians were shown in Table 3, respectively. For Europeans, genetically predicted getting up in morning reduced the risk of epilepsy (OR=0.354, 95%CI: 0.212-0.589), whereas genetically predicted evening person (chronotype) increased the risk of epilepsy (OR=1.371, 95%CI: 1.082-1.739) (Table 3). Moreover, genetically predicted getting up in morning decreased the risk of generalized epilepsy in Europeans (OR=0.256, 95%CI: 0.101-0.651), while genetically predicted evening person (chronotype) increased the risk of generalized epilepsy in Europeans (OR=1.618, 95%CI: 1.061-2.467). However, no significant associations were found between genetically predicted sleeplessness/insomnia, sleep duration, nap during day, and daytime dozing/sleeping (narcolepsy) and the risk of epilepsy, focal epilepsy, and generalized epilepsy (P>0.05). For the effect of sleep traits on epilepsy risk, the results of the weighted median and weighted mode methods were consistent with those of IVW (Supplement Table 3). The MR-PRESSO and Radial test showed that the direction of sleep traits on epilepsy risk remained unchanged in analyses with abnormal SNPs after the outliers were removed (Supplement Table 4).
For East Asians, genetically predicted sleeplessness/insomnia increased the risk of epilepsy (OR=1.381, 95%CI: 1.039-1.837), whereas no significant associations were observed between genetically predicted sleep apnoea, sleep duration, evening person (chronotype), and daytime dozing/sleeping (narcolepsy) and the risk of epilepsy (P>0.05) (Table 3). The results of the weighted median and weighted mode methods were consistent with those of IVW in East Asians (Supplement Table 5). The leave-one-out analysis indicated that the causal associations between sleep traits and epilepsy risk in Europeans and East Asians were not caused by any individual SNP (Supplementary Figures 1 and 2). The scatter plot for the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians were listed in Figure 2.
Discussion
We analyzed the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians, respectively. The results showed that genetically predicted getting up in morning reduced the risk of epilepsy and generalized epilepsy in Europeans, while genetically predicted evening person (chronotype) increased the risk of epilepsy and generalized epilepsy in Europeans. For East Asians, genetically predicted sleeplessness/insomnia increased the risk of epilepsy. Moreover, no significant relationships were observed between genetically predicted sleeplessness/insomnia, sleep duration, nap during day, and daytime dozing/sleeping (narcolepsy) and the risk of epilepsy, focal epilepsy, and generalized epilepsy in Europeans.
The pathophysiology of epilepsy is primarily related to membrane excitatory dysfunction and an imbalance between excitatory and inhibitory neurotransmitters in neuronal circuits [22]. There is an interaction between sleep and epilepsy, and the occurrence of epilepsy can trigger the accumulation of reactive oxygen species (ROS), which can disrupt neuronal and glial function, leading to subsequent sleep changes [23,24]. Conversely, sleep deprivation can lead to an accumulation of ROS, which can lead to an increased chance of epilepsy [25]. The current study investigated the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians, respectively. For Europeans, getting up in morning reduced the risk of epilepsy, whereas evening person (chronotype) increased the risk of epilepsy. Moreover, sleeplessness/insomnia increased the risk of epilepsy in East Asians. The trait “getting up in morning” represents how easy it is for an individual to get up in the morning, and the trait “evening person (chronotype)” represents the chronological changes in the sleep process of an individual. A GWAS showed a strong genetic correlation and many common genetic underpinnings between early chronotype and getting up easier in the morning, suggesting a common biological mechanism for circadian regulation of these two traits [26]. Morning/evening person (chronotype) is a manifestation of a disordered biological rhythm influenced by social and environmental factors [27]. Individuals shift from a morning person to an evening person chronotype, exhibiting a delayed circadian rhythm. Morning chronotype was reported to exhibit longer telomeres than evening chronotype [28]. Individuals with an evening chronotype typically sleep late and have difficulty waking up in the morning, which can lead to sleep deprivation, further contributing to increased inflammation and metabolic disruption related to cellular circadian rhythms [29,30].
Sleep deprivation is a common cause of seizures in people with epilepsy [31]. Our results indicated that sleeplessness/insomnia increased the risk of epilepsy in East Asians. Insomnia is recognized as a disorder of hyperarousal associated with increased somatic, cognitive, and cortical activation [32,33]. Patients with insomnia may experience physiologic hyperarousal in both the central (cortical) and peripheral (autonomic) nervous systems [33]. Epilepsy patients with insomnia are more likely to have seizures than those without insomnia [6]. Insomnia may affect the occurrence of epilepsy through the regulation of circadian rhythm [34]. However, the specific biological mechanisms by which sleep traits affect epilepsy are not fully understood. Two main mechanisms have been reported to be involved in epilepsy that may result from circadian rhythm changes [5]. First, core clock genes (e.g., aryl hydrocarbon receptor nuclear translocation-like (ARNT) and biological clock regulator are directly or indirectly involved in epileptic excitability and influence the expression of other epilepsy-related genes [35,36]. Second, circadian changes in the mammalian target of rapamycin (mTOR) pathway may contribute to epileptic activity. The mTOR pathway is a major regulatory system for cellular function, and aberrant mTOR signaling controlled by the circadian system has been associated with a variety of neurological disorders, including epilepsy [9,37,38]. The mechanisms underlying the effect of sleep traits on epilepsy risk may need to be further explored.
This current study analyzed the causal relationship between different sleep traits and epilepsy risk in Europeans and East Asians, respectively. In this study, we used MR analysis to minimize the influence of confounding factors in traditional epidemiology. Moreover, we analyzed genetic data based on populations of European and East Asian ancestry separately, which can reduce bias due to ethnicity. However, several limitations should be noted. First, the lack of individual data prevented further analysis of causal associations between sleep traits and the risk of epilepsy and its subtypes in different populations (e.g., age, sex). Second, we did not perform bidirectional MR analyses because SNPs were not screened for when epilepsy was used as an exposure. However, we performed the MR Steiger directionality test and the results indicated that the causal direction of the relationship from sleep traits to epilepsy was in the correct direction. Third, some sleep traits [e.g., sleep apnoea, sleep duration (undersleepers), sleep duration (oversleepers)] were not analyzed because they were not screened for SNPs that could be used for analysis.
Conclusions
For Europeans, genetically predicted getting up in morning decreased the risk of epilepsy, while genetically predicted evening person (chronotype) increased the risk of epilepsy. Moreover, genetically predicted sleeplessness/insomnia increased the risk of epilepsy in East Asians. Future studies need to investigate the mechanisms by which sleep traits affect epilepsy risk.
Supplementary Materials
The following supporting information can be downloaded at the website of this paper posted on Preprints.org.
Funding
This work was supported by the China Association Against Epilepsy Research Fund (No. CJ-2022-021), Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-052B).
Authors’ contributions
Xun Li and Wei Yue designed the study. Xun Li wrote the manuscript. Xun Li and Wei Yue collected, analyzed, and interpreted the data. Wei Yue critically reviewed, edited, and approved the manuscript. All authors read and approved the final manuscript.
Consent for publication
Not applicable.
Ethics approval and consent to participate
This study was based on a secondary analysis of publicly available data and was exempt from additional ethical approval. The need for informed consent was waived. All methods were performed in accordance with the relevant guidelines and regulations.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are available in the IEU Open GWAS project, https://www.ebi.ac.uk/gwas/.
Acknowledgements
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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Figure 1.
Figure 1. The assumptions of Mendelian randomization (MR) analysis for this study.
Figure 2.
Figure 2. The scatter plot for the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians. (A) getting up in morning and epilepsy risk in Europeans; (B) morning/evening person (chronotype) and epilepsy risk in Europeans; (C) getting up in morning and generalized epilepsy risk in Europeans; (D) morning/evening person (chronotype) and generalized epilepsy risk in Europeans; (E) sleeplessness/insomnia and epilepsy risk in East Asians.
Figure 2.
Figure 2. The scatter plot for the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians. (A) getting up in morning and epilepsy risk in Europeans; (B) morning/evening person (chronotype) and epilepsy risk in Europeans; (C) getting up in morning and generalized epilepsy risk in Europeans; (D) morning/evening person (chronotype) and generalized epilepsy risk in Europeans; (E) sleeplessness/insomnia and epilepsy risk in East Asians.
Table 1.
The screening process and strength tests for SNPs associated with sleep traits and epilepsy in Europeans.
Table 1.
The screening process and strength tests for SNPs associated with sleep traits and epilepsy in Europeans.
| Outcome and exposure | Selected SNP (P<5E-08) (n) | Omitted LD SNP (n) | Drop palindromic SNP (n) |
F-value | R2(%) |
|---|---|---|---|---|---|
| Epilepsy | |||||
| Getting up in morning | 5953 | 40 | 38 | 40 | 0.47 |
| Sleeplessness/insomnia | 2654 | 42 | 39 | 33 | 0.41 |
| Sleep duration | 5751 | 71 | 69 | 32 | 0.67 |
| Sleep duration (undersleepers) | 1 | 0 | 0 | - | - |
| Sleep duration (oversleepers) | 2 | 0 | 0 | - | - |
| Sleep apnoea | 0 | 0 | 0 | - | - |
| Nap during day | 8636 | 94 | 86 | 34 | 0.94 |
| Morning/evening person (chronotype) | 13669 | 161 | 150 | 38 | 1.78 |
| Daytime dozing/sleeping (narcolepsy) | 4187 | 31 | 31 | 32 | 0.30 |
| Focal epilepsy | |||||
| Getting up in morning | 5953 | 40 | 38 | 40 | 0.47 |
| Sleeplessness/insomnia | 2654 | 42 | 39 | 33 | 0.41 |
| Sleep duration | 5751 | 71 | 69 | 32 | 0.67 |
| Sleep duration (undersleepers) | 1 | 0 | 0 | - | - |
| Sleep duration (oversleepers) | 2 | 0 | 0 | - | - |
| Sleep apnoea | 0 | 0 | 0 | - | - |
| Nap during day | 8636 | 94 | 86 | 34 | 0.94 |
| Morning/evening person (chronotype) | 13669 | 161 | 150 | 38 | 1.78 |
| Daytime dozing/sleeping (narcolepsy) | 4187 | 31 | 31 | 32 | 0.30 |
| Generalized epilepsy | |||||
| Getting up in morning | 5953 | 40 | 38 | 40 | 0.47 |
| Sleeplessness/insomnia | 2654 | 42 | 39 | 33 | 0.41 |
| Sleep duration | 5751 | 71 | 69 | 32 | 0.67 |
| Sleep duration (undersleepers) | 1 | 0 | 0 | - | - |
| Sleep duration (oversleepers) | 2 | 0 | 0 | - | - |
| Sleep apnoea | 0 | 0 | 0 | - | - |
| Nap during day | 8636 | 94 | 86 | 34 | 0.94 |
| Morning/evening person (chronotype) | 13669 | 161 | 150 | 38 | 1.78 |
| Daytime dozing/sleeping (narcolepsy) | 4187 | 31 | 31 | 32 | 0.30 |
Note: SNPs, single nucleotide polymorphisms; LD, linkage disequilibrium.
Table 2.
The results of the horizontal pleiotropy and heterogeneity tests for SNPs.
| Outcome and exposure | Horizontal pleiotropic test | Casual direction test | Heterogeneity test | |||||
|---|---|---|---|---|---|---|---|---|
| Egger intercept | P | MR steiger | P | MR Egger Q | P | IVW Q | P | |
| Europeans | ||||||||
| Epilepsy | ||||||||
| Getting up in morning | -0.014 | 0.350 | TRUE | 2.97E-66 | 46.615 | 0.111 | 47.779 | 0.110 |
| Sleeplessness/insomnia | -0.008 | 0.428 | TRUE | 7.89E-81 | 21.302 | 0.982 | 21.945 | 0.983 |
| Sleep duration | -0.017 | 0.123 | TRUE | 8.83E-106 | 76.710 | 0.195 | 79.506 | 0.161 |
| Nap during day | 0.012 | 0.179 | TRUE | 1.42E-157 | 90.510 | 0.294 | 92.486 | 0.271 |
| Morning/evening person (chronotype) | -0.001 | 0.823 | TRUE | 2.91E-283 | 180.538 | 0.035 | 180.599 | 0.040 |
| Daytime dozing/sleeping (narcolepsy) | 0.008 | 0.693 | TRUE | 7.90E-48 | 36.812 | 0.151 | 37.015 | 0.177 |
| Focal epilepsy | ||||||||
| Getting up in morning | 0.007 | 0.833 | TRUE | 7.34E-90 | 30.056 | 0.746 | 30.101 | 0.782 |
| Sleeplessness/insomnia | 0.006 | 0.823 | TRUE | 1.39E-86 | 29.738 | 0.796 | 29.789 | 0.827 |
| Sleep duration | -0.003 | 0.909 | TRUE | 8.00E-132 | 66.665 | 0.489 | 66.678 | 0.523 |
| Nap during day | 0.024 | 0.253 | TRUE | 3.94E-198 | 64.089 | 0.948 | 65.416 | 0.943 |
| Morning/evening person (chronotype) | -0.008 | 0.629 | TRUE | 0 | 182.183 | 0.029 | 182.473 | 0.032 |
| Daytime dozing/sleeping (narcolepsy) | 0.030 | 0.585 | TRUE | 9.87E-52 | 46.276 | 0.022 | 46.763 | 0.026 |
| Generalized epilepsy | ||||||||
| Getting up in morning | -0.024 | 0.338 | TRUE | 1.43E-88 | 28.636 | 0.804 | 29.580 | 0.802 |
| Sleeplessness/insomnia | -0.020 | 0.290 | TRUE | 3.51E-83 | 35.056 | 0.560 | 36.210 | 0.552 |
| Sleep duration | -0.021 | 0.262 | TRUE | 2.27E-135 | 59.197 | 0.740 | 60.475 | 0.730 |
| Nap during day | 0.019 | 0.289 | TRUE | 6.22E-175 | 111.083 | 0.026 | 112.587 | 0.024 |
| Morning/evening person (chronotype) | 0.004 | 0.704 | TRUE | 0 | 170.123 | 0.103 | 170.289 | 0.112 |
| Daytime dozing/sleeping (narcolepsy) | -0.010 | 0.753 | TRUE | 2.02E-59 | 30.470 | 0.391 | 30.576 | 0.436 |
| East Asians | ||||||||
| Epilepsy | ||||||||
| Sleep apnoea | - | - | TRUE | 6.44E-06 | 0.091 | 0.763 | - | - |
| Sleep duration | -0.082 | 0.419 | TRUE | 2.03E-27 | 1.765 | 0.623 | 0.745 | 0.689 |
| Morning/evening person (chronotype) | -0.331 | 0.493 | TRUE | 1.33E-15 | 3.180 | 0.204 | 1.555 | 0.212 |
| Sleeplessness/insomnia | -0.055 | 0.341 | TRUE | 7.72E-36 | 2.668 | 0.849 | 1.561 | 0.906 |
| Daytime dozing/sleeping (narcolepsy) | 0.116 | 0.223 | TRUE | 7.09E-30 | 5.691 | 0.223 | 3.193 | 0.363 |
Note: SNPs, single nucleotide polymorphisms; MR, Mendelian randomization; IVW, inverse-variance weighted.
Table 3.
The IVW results of the relationship between sleep traits and epilepsy risk in Europeans and East Asians.
Table 3.
The IVW results of the relationship between sleep traits and epilepsy risk in Europeans and East Asians.
| Variables | SNPs (n) | Fixed effects | Multiplicative random effects | ||
|---|---|---|---|---|---|
| OR (95%CI) | P | OR (95%CI) | P | ||
| Europeans | |||||
| Epilepsy | |||||
| Getting up in morning | 38 | 0.354 (0.212-0.589) | 0.000 | 0.354 (0.198-0.631) | 0.000 |
| Sleeplessness/insomnia | 39 | 1.367 (0.770-2.427) | 0.285 | 1.367 (0.884-2.115) | 0.160 |
| Sleep duration | 69 | 0.950 (0.616-1.464) | 0.815 | 0.950 (0.595-1.516) | 0.829 |
| Nap during day | 86 | 1.152 (0.716-1.852) | 0.559 | 1.152 (0.702-1.891) | 0.576 |
| Morning/evening person (chronotype) | 150 | 1.371 (1.105-1.702) | 0.004 | 1.371 (1.082-1.739) | 0.009 |
| Daytime dozing/sleeping (narcolepsy) | 31 | 1.305 (0.487-3.494) | 0.597 | 1.305 (0.437-3.897) | 0.634 |
| Focal epilepsy | |||||
| Getting up in morning | 38 | 0.304 (0.084-1.102) | 0.070 | 0.304 (0.095-0.971) | 0.045 |
| Sleeplessness/insomnia | 39 | 0.766 (0.179-3.268) | 0.719 | 0.766 (0.212-2.768) | 0.684 |
| Sleep duration | 69 | 0.811 (0.272-2.419) | 0.707 | 0.811 (0.275-2.394) | 0.704 |
| Nap during day | 86 | 0.405 (0.122-1.343) | 0.139 | 0.405 (0.141-1.159) | 0.092 |
| Morning/evening person (chronotype) | 150 | 1.723 (0.999-2.971) | 0.051 | 1.723 (0.942-3.149) | 0.077 |
| Daytime dozing/sleeping (narcolepsy) | 31 | 0.407 (0.034-4.903) | 0.479 | 0.407 (0.018-9.099) | 0.571 |
| Generalized epilepsy | |||||
| Getting up in morning | 38 | 0.256 (0.101-0.651) | 0.004 | 0.256 (0.111-0.590) | 0.001 |
| Sleeplessness/insomnia | 39 | 2.223 (0.777-6.355) | 0.136 | 2.223 (0.797-6.197) | 0.127 |
| Sleep duration | 69 | 1.130 (0.512-2.494) | 0.762 | 1.130 (0.536-2.384) | 0.748 |
| Nap during day | 86 | 0.729 (0.306-1.737) | 0.475 | 0.729 (0.268-1.981) | 0.535 |
| Morning/evening person (chronotype) |
150 | 1.618 (1.090-2.401) | 0.017 | 1.618 (1.061-2.467) | 0.025 |
| Daytime dozing/sleeping (narcolepsy) | 31 | 1.584 (0.261-9.604) | 0.617 | 1.584 (0.257-9.771) | 0.620 |
| East Asians | |||||
| Epilepsy | |||||
| Sleep apnoea | 2 | 0.970 (0.849-1.109) | 0.659 | 0.970 (0.932-1.010) | 0.143 |
| Sleep duration | 4 | 1.111 (0.827-1.492) | 0.485 | 1.111 (0.886-1.393) | 0.363 |
| Morning/evening person (chronotype) | 3 | 1.112 (0.852-1.450) | 0.434 | 1.112 (0.795-1.554) | 0.535 |
| Sleeplessness/insomnia | 7 | 1.381 (1.039-1.837) | 0.026 | 1.381 (1.142-1.671) | 0.001 |
| Daytime dozing/sleeping (narcolepsy) | 5 | 0.899 (0.577-1.402) | 0.639 | 0.899 (0.529-1.527) | 0.694 |
Note: SNPs, single nucleotide polymorphisms; IVW, inverse-variance weighted; OR, odds ratio; CI, confidence interval.
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