Association between sleep traits and epilepsy risk: a two-sample Mendelian randomization study

Association between sleep traits and epilepsy risk: a two-sample Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association between sleep traits and epilepsy risk: a two-sample Mendelian randomization study Xun Li, Wei Yue This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5665142/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. sleep traits epilepsy causal link Mendelian randomization populations Figures Figure 1 Figure 2 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 28.9–74.4% 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 (Fig. 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) (r 2 = 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 (R 2 ), and SNPs with an F-statistic less than 10 were considered weak instrument variables. The calculations of F-statistic [ 20 ] and R 2 [ 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). 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. 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 R 2 (%) 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. 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 Figs. 1 and 2). The scatter plot for the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians were listed in Fig. 2 . 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. 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. Declarations 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/. Clinical trial number : not applicable Competing interests The authors declare that they have no competing interests. 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. Acknowledgements Not applicable. References Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet (London England). 2019;393(10172):689–701. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):792–802. Fishbein AB, Knutson KL, Zee PC. Circadian disruption and human health. J Clin Investig 2021, 131(19). Abbott SM, Malkani RG, Zee PC. 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Valeriia Haberland, George Davey Smith et al: The MRC IEU OpenGWAS data infrastructure. bioRxiv. 2020;08:244293v244291. Jones SE, Tyrrell J, Wood AR, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Hu Y, Teder-Laving M, Hayward C, et al. Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. PLoS Genet. 2016;12(8):e1006125. Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73–9. Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, Narita A, Konuma T, Yamamoto K, Akiyama M, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415–24. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40(4):304–14. Burgess S, Thompson SG. Bias in causal estimates from Mendelian randomization studies with weak instruments. Stat Med. 2011;30(11):1312–23. Wang Y, Gao L, Lang W, Li H, Cui P, Zhang N, Jiang W. Serum Calcium Levels and Parkinson's Disease: A Mendelian Randomization Study. Front Genet. 2020;11:824. Staley K. Molecular mechanisms of epilepsy. Nat Neurosci. 2015;18(3):367–72. Patel M. Targeting Oxidative Stress in Central Nervous System Disorders. Trends Pharmacol Sci. 2016;37(9):768–78. Ishii T, Takanashi Y, Sugita K, Miyazawa M, Yanagihara R, Yasuda K, Onouchi H, Kawabe N, Nakata M, Yamamoto Y, et al. Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain. Aging Cell. 2017;16(1):39–51. Terrone G, Balosso S, Pauletti A, Ravizza T, Vezzani A. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology. 2020;167:107742. Fei CJ, Li ZY, Ning J, Yang L, Wu BS, Kang JJ, Liu WS, He XY, You J, Chen SD, et al. Exome sequencing identifies genes associated with sleep-related traits. Nat Hum Behav. 2024;8(3):576–89. Hu J, Lu J, Lu Q, Weng W, Guan Z, Wang Z. Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length. Commun biology. 2023;6(1):1014. Wynchank D, Bijlenga D, Penninx BW, Lamers F, Beekman AT, Kooij JJS, Verhoeven JE. Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length. Sleep 2019, 42(10). Adan A, Archer SN, Hidalgo MP, Di Milia L, Natale V, Randler C. Circadian typology: a comprehensive review. Chronobiol Int. 2012;29(9):1153–75. van der Merwe C, Münch M, Kruger R. Chronotype Differences in Body Composition, Dietary Intake and Eating Behavior Outcomes: A Scoping Systematic Review. Adv Nutr (Bethesda Md). 2022;13(6):2357–405. Wassenaar M, Kasteleijn-Nolst Trenité DG, de Haan GJ, Carpay JA, Leijten FS. Seizure precipitants in a community-based epilepsy cohort. J Neurol. 2014;261(4):717–24. Riemann D, Spiegelhalder K, Feige B, Voderholzer U, Berger M, Perlis M, Nissen C. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev. 2010;14(1):19–31. Levenson JC, Kay DB, Buysse DJ. The pathophysiology of insomnia. Chest. 2015;147(4):1179–92. Meyer N, Harvey AG, Lockley SW, Dijk DJ. Circadian rhythms and disorders of the timing of sleep. Lancet (London England). 2022;400(10357):1061–78. Gerstner JR, Smith GG, Lenz O, Perron IJ, Buono RJ, Ferraro TN. BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice. Front Syst Neurosci. 2014;8:121. Li P, Fu X, Smith NA, Ziobro J, Curiel J, Tenga MJ, Martin B, Freedman S, Cea-Del Rio CA, Oboti L, et al. Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy. Neuron. 2017;96(2):387–e401386. Ramanathan C, Kathale ND, Liu D, Lee C, Freeman DA, Hogenesch JB, Cao R, Liu AC. mTOR signaling regulates central and peripheral circadian clock function. PLoS Genet. 2018;14(5):e1007369. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960–76. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5665142","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":393617984,"identity":"c3b4c60a-7a1f-44f8-98ce-c06338322c17","order_by":0,"name":"Xun Li","email":"","orcid":"","institution":"Tianjin Huanhu Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xun","middleName":"","lastName":"Li","suffix":""},{"id":393617985,"identity":"5bdbae53-5905-4f66-a251-36a1cc4ff5c6","order_by":1,"name":"Wei Yue","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYNACA5t6fgaGxAcJFTVEa0lLkGxjSDZ4cOYY0dYcTjA4xsAm+bCFmQjzbyQfk/hQkJYnOb/hWUViAxsDf3t3AgEtaWmSMwxsivnZGNJuJO6QYZA4c3YDAS05Zrd5DNIYZ7aBtJxhYzCQyCWkJf/b7T8Ghxk3HGNIK0hsYyZGSw7bbQaDw4kgLQxEaZE888z8Z49BmrFkW0KyRMKZYzwE/cJ3PPmxwY8/NnL8zGcSP/6oqJHjb+/Fr0XhAJzJkwAm8SoHAfkGOJP9AE5Vo2AUjIJRMLIBAHEbTuP7QUgNAAAAAElFTkSuQmCC","orcid":"","institution":"Tianjin Huanhu Hospital","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Yue","suffix":""}],"badges":[],"createdAt":"2024-12-18 01:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5665142/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5665142/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72238894,"identity":"afe503a6-f7b2-40d9-8d51-b412e26f71b2","added_by":"auto","created_at":"2024-12-24 06:20:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1830572,"visible":true,"origin":"","legend":"\u003cp\u003eThe assumptions of Mendelian randomization (MR) analysis for this study.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5665142/v1/7b90b42e604d20a7b30ad273.png"},{"id":72238766,"identity":"c1a72043-20f1-40ec-9dc8-1e0aef2613d1","added_by":"auto","created_at":"2024-12-24 06:12:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":403653,"visible":true,"origin":"","legend":"\u003cp\u003eThe 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.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5665142/v1/1695ea015e7ab13d033edc86.png"},{"id":72240121,"identity":"ff1fab39-3e6d-4b83-a85c-6a3c72fe375f","added_by":"auto","created_at":"2024-12-24 06:36:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3001818,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5665142/v1/65c76045-1610-4f1a-860e-3823e751d749.pdf"},{"id":72238779,"identity":"e4d58b8f-0c9e-4b3a-b25d-558653413572","added_by":"auto","created_at":"2024-12-24 06:12:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7031763,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-5665142/v1/19bf94c4ecf37f4f602b3183.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between sleep traits and epilepsy risk: a two-sample Mendelian randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpilepsy is one of the most common serious central nervous system disorders, affecting more than 70\u0026nbsp;million people worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Epilepsy is characterized by sustained easily occurring spontaneous seizures with neurobiological, cognitive and psychosocial consequences [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Identifying modifiable risk factors related to epilepsy is critical to preventing the development of epilepsy and reducing the burden of disease.\u003c/p\u003e \u003cp\u003eSleep is an important part of human health, and circadian rhythm disruption can increase the risk of several diseases, including the nervous system [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There is a complex bidirectional relationship between sleep and epilepsy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], with insomnia rates ranging from 28.9\u0026ndash;74.4% and significantly worse sleep quality in patients with epilepsy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Circadian rhythms may influence neurological function by regulating blood-brain barrier integrity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and may also be involved in the development of epilepsy by modulating the mammalian target of rapamycin (mTOR) pathway [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Chronotype is a simple indicator of an individual\u0026rsquo;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) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Chronotype preference may also influence blood drug concentration and efficacy by influencing the duration of antiepileptic drug administration [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) uses genetic variation as an instrumental variable to explore the causal association between exposure and disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. 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.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source and study design\u003c/h2\u003e \u003cp\u003eThis 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 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/datasets/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/datasets/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), which is a complete genome-wide association study (GWAS) summary dataset, and the relevant genetic variant data can be downloaded as open-source files [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. 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 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). 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.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGenetic instrumental variable\u003c/h3\u003e\n\u003cp\u003eThe 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\u0026rsquo;s touchscreen questionnaire (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://biobank.ndph.ox.ac.uk/showcase/refer.cgi?id=113241\u003c/span\u003e\u003cspan address=\"https://biobank.ndph.ox.ac.uk/showcase/refer.cgi?id=113241\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). 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 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], 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 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], 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.\u003c/p\u003e \u003cp\u003eFor East Asians, SNPs associated with sleep apnoea from a GWAS [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] 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.\u003c/p\u003e \u003cp\u003eThe 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 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://r7.finngen.fi/\u003c/span\u003e\u003cspan address=\"https://r7.finngen.fi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). 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\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eSelection of instrumental variables\u003c/h3\u003e\n\u003cp\u003eTo 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 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e or \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e). Then, SNPs with linkage disequilibrium (LD) (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.001, clump distance\u0026thinsp;=\u0026thinsp;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 \u0026ldquo;harmonise_data\u0026rdquo; function in the TwoSampleMR package, so that the exposure and the outcome had the same allele.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMultiple 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 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], 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.\u003c/p\u003e \u003cp\u003eSeveral 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 (R\u003csup\u003e2\u003c/sup\u003e), and SNPs with an F-statistic less than 10 were considered weak instrument variables. The calculations of F-statistic [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and R\u003csup\u003e2\u003c/sup\u003e [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] 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\u0026rsquo;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 \u0026ldquo;TwoSampleMR\u0026rdquo; package in R version 4.1.3 software (Institute for Statistics and Mathematics, Vienna, Austria). A P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of instrumental variables\u003c/h2\u003e \u003cp\u003eThe screening process and strength tests for SNPs associated with sleep traits and epilepsy were listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (Europeans) and Supplement Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (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 (\u0026gt;\u0026thinsp;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\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The horizontal pleiotropy test demonstrated that there was no horizontal pleiotropy among these SNPs (P\u0026thinsp;\u0026gt;\u0026thinsp;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\u0026thinsp;\u0026lt;\u0026thinsp;0.05). For East Asians, there was no heterogeneity among these SNPs (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Moreover, the MR Steiger directionality test demonstrated that the direction of the relationship between sleep traits and epilepsy risk was \u0026ldquo;TURE\u0026rdquo; in both Europeans and East Asians, suggesting a causal relationship.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe screening process and strength tests for SNPs associated with sleep traits and epilepsy in Europeans.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome and exposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSelected SNP (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5E-08) (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOmitted LD SNP (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDrop\u003c/p\u003e \u003cp\u003epalindromic SNP (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2654\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration (undersleepers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration (oversleepers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep apnoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFocal epilepsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2654\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration (undersleepers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration (oversleepers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep apnoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGeneralized epilepsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2654\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration (undersleepers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration (oversleepers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep apnoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eNote: SNPs, single nucleotide polymorphisms; LD, linkage disequilibrium.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe results of the horizontal pleiotropy and heterogeneity tests for SNPs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome and exposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eHorizontal pleiotropic test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eCasual direction test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eHeterogeneity test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEgger intercept\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR steiger\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMR Egger Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIVW Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eEuropeans\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.97E-66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46.615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e47.779\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.428\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.89E-81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.982\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e21.945\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.83E-106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e76.710\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e79.506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.42E-157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e90.510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e92.486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.91E-283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e180.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e180.599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.693\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.90E-48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.812\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFocal epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.34E-90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e30.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.782\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.39E-86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29.738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.796\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.789\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.827\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.00E-132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e66.678\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.94E-198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.948\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e65.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e182.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e182.473\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.87E-52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46.276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e46.763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneralized epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.43E-88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.580\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.802\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.51E-83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e36.210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.27E-135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59.197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60.475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.730\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.22E-175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e111.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e112.587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e170.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e170.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.753\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.02E-59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.470\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.391\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e30.576\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.436\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEast Asians\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep apnoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.44E-06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.03E-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.765\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.623\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.689\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.493\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.33E-15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.212\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.72E-36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.668\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.849\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.561\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.906\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRUE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.09E-30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eNote: SNPs, single nucleotide polymorphisms; MR, Mendelian randomization; IVW, inverse-variance weighted.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCausal relationship between sleep traits and epilepsy risk\u003c/h3\u003e\n\u003cp\u003eThe IVW results of the relationship between sleep traits and epilepsy risk in Europeans and East Asians were shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, respectively. For Europeans, genetically predicted getting up in morning reduced the risk of epilepsy (OR\u0026thinsp;=\u0026thinsp;0.354, 95%CI: 0.212\u0026ndash;0.589), whereas genetically predicted evening person (chronotype) increased the risk of epilepsy (OR\u0026thinsp;=\u0026thinsp;1.371, 95%CI: 1.082\u0026ndash;1.739) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Moreover, genetically predicted getting up in morning decreased the risk of generalized epilepsy in Europeans (OR\u0026thinsp;=\u0026thinsp;0.256, 95%CI: 0.101\u0026ndash;0.651), while genetically predicted evening person (chronotype) increased the risk of generalized epilepsy in Europeans (OR\u0026thinsp;=\u0026thinsp;1.618, 95%CI: 1.061\u0026ndash;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\u0026thinsp;\u0026gt;\u0026thinsp;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\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). 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\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eFor East Asians, genetically predicted sleeplessness/insomnia increased the risk of epilepsy (OR\u0026thinsp;=\u0026thinsp;1.381, 95%CI: 1.039\u0026ndash;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\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The results of the weighted median and weighted mode methods were consistent with those of IVW in East Asians (Supplement Table\u0026nbsp;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 Figs.\u0026nbsp;1 and 2). The scatter plot for the causal relationship between sleep traits and epilepsy risk in Europeans and East Asians were listed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe IVW results of the relationship between sleep traits and epilepsy risk in Europeans and East Asians.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSNPs (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eFixed effects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eMultiplicative random effects\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eEuropeans\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEpilepsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.354 (0.212\u0026ndash;0.589)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.354 (0.198\u0026ndash;0.631)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.367 (0.770\u0026ndash;2.427)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.367 (0.884\u0026ndash;2.115)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.950 (0.616\u0026ndash;1.464)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.815\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.950 (0.595\u0026ndash;1.516)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.829\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.152 (0.716\u0026ndash;1.852)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.559\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.152 (0.702\u0026ndash;1.891)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.576\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening\u003c/p\u003e \u003cp\u003eperson (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.371 (1.105\u0026ndash;1.702)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.371 (1.082\u0026ndash;1.739)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.305 (0.487\u0026ndash;3.494)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.305 (0.437\u0026ndash;3.897)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.634\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFocal epilepsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.304 (0.084\u0026ndash;1.102)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.304 (0.095\u0026ndash;0.971)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.766 (0.179\u0026ndash;3.268)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.719\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.766 (0.212\u0026ndash;2.768)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.811 (0.272\u0026ndash;2.419)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.811 (0.275\u0026ndash;2.394)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.704\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.405 (0.122\u0026ndash;1.343)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.405 (0.141\u0026ndash;1.159)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening\u003c/p\u003e \u003cp\u003eperson (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.723 (0.999\u0026ndash;2.971)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.723 (0.942\u0026ndash;3.149)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.407 (0.034\u0026ndash;4.903)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.479\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.407 (0.018\u0026ndash;9.099)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.571\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGeneralized epilepsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGetting up in morning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.256 (0.101\u0026ndash;0.651)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.256 (0.111\u0026ndash;0.590)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.223 (0.777\u0026ndash;6.355)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.223 (0.797\u0026ndash;6.197)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.130 (0.512\u0026ndash;2.494)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.762\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.130 (0.536\u0026ndash;2.384)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.748\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNap during day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.729 (0.306\u0026ndash;1.737)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.729 (0.268\u0026ndash;1.981)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening\u003c/p\u003e \u003cp\u003eperson (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.618 (1.090\u0026ndash;2.401)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.618 (1.061\u0026ndash;2.467)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.584 (0.261\u0026ndash;9.604)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.617\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.584 (0.257\u0026ndash;9.771)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.620\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEast Asians\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEpilepsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep apnoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.970 (0.849\u0026ndash;1.109)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.659\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.970 (0.932\u0026ndash;1.010)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.143\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.111 (0.827\u0026ndash;1.492)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.111 (0.886\u0026ndash;1.393)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning/evening person (chronotype)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.112 (0.852\u0026ndash;1.450)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.112 (0.795\u0026ndash;1.554)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleeplessness/insomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.381 (1.039\u0026ndash;1.837)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.381 (1.142\u0026ndash;1.671)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaytime dozing/sleeping (narcolepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.899 (0.577\u0026ndash;1.402)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.899 (0.529\u0026ndash;1.527)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eNote: SNPs, single nucleotide polymorphisms; IVW, inverse-variance weighted; OR, odds ratio; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe 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.\u003c/p\u003e \u003cp\u003eThe pathophysiology of epilepsy is primarily related to membrane excitatory dysfunction and an imbalance between excitatory and inhibitory neurotransmitters in neuronal circuits [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Conversely, sleep deprivation can lead to an accumulation of ROS, which can lead to an increased chance of epilepsy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. 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 \u0026ldquo;getting up in morning\u0026rdquo; represents how easy it is for an individual to get up in the morning, and the trait \u0026ldquo;evening person (chronotype)\u0026rdquo; 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 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Morning/evening person (chronotype) is a manifestation of a disordered biological rhythm influenced by social and environmental factors [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSleep deprivation is a common cause of seizures in people with epilepsy [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Patients with insomnia may experience physiologic hyperarousal in both the central (cortical) and peripheral (autonomic) nervous systems [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Epilepsy patients with insomnia are more likely to have seizures than those without insomnia [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Insomnia may affect the occurrence of epilepsy through the regulation of circadian rhythm [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The mechanisms underlying the effect of sleep traits on epilepsy risk may need to be further explored.\u003c/p\u003e \u003cp\u003eThis 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.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFor 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis 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.\u0026nbsp;All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available in the IEU Open GWAS project, https://www.ebi.ac.uk/gwas/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis 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).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXun 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet (London England). 2019;393(10172):689\u0026ndash;701.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):792\u0026ndash;802.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFishbein AB, Knutson KL, Zee PC. Circadian disruption and human health. J Clin Investig 2021, 131(19).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbott SM, Malkani RG, Zee PC. 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Circadian rhythms and disorders of the timing of sleep. Lancet (London England). 2022;400(10357):1061\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerstner JR, Smith GG, Lenz O, Perron IJ, Buono RJ, Ferraro TN. BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice. Front Syst Neurosci. 2014;8:121.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi P, Fu X, Smith NA, Ziobro J, Curiel J, Tenga MJ, Martin B, Freedman S, Cea-Del Rio CA, Oboti L, et al. Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy. Neuron. 2017;96(2):387\u0026ndash;e401386.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamanathan C, Kathale ND, Liu D, Lee C, Freeman DA, Hogenesch JB, Cao R, Liu AC. mTOR signaling regulates central and peripheral circadian clock function. PLoS Genet. 2018;14(5):e1007369.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"sleep traits, epilepsy, causal link, Mendelian randomization, populations","lastPublishedDoi":"10.21203/rs.3.rs-5665142/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5665142/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSleep 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.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eExposure- [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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFor Europeans, genetically predicted getting up in morning decreased the risk of epilepsy (OR\u0026thinsp;=\u0026thinsp;0.354, 95%CI: 0.212\u0026ndash;0.589) and generalized epilepsy (OR\u0026thinsp;=\u0026thinsp;0.256, 95%CI: 0.101\u0026ndash;0.651), whereas genetically predicted evening person (chronotype) increased the risk of epilepsy (OR\u0026thinsp;=\u0026thinsp;1.371, 95%CI: 1.082\u0026ndash;1.739) and generalized epilepsy (OR\u0026thinsp;=\u0026thinsp;1.618, 95%CI: 1.061\u0026ndash;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\u0026thinsp;=\u0026thinsp;1.381, 95%CI: 1.039\u0026ndash;1.837).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThere 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.\u003c/p\u003e","manuscriptTitle":"Association between sleep traits and epilepsy risk: a two-sample Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 06:12:29","doi":"10.21203/rs.3.rs-5665142/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"516144b9-14ca-40ee-8ffc-d21bc35263b1","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-24T06:12:29+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-24 06:12:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5665142","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5665142","identity":"rs-5665142","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}