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Background: Observational research suggests that hypotension is a potential hazard factor of delirium. Nevertheless, previous observational articles are limited in their ability to establish causality between hypotension and delirium. The present study was sought to explore the genetic causal relationship between these two conditions using two-sample Mendelian randomization (MR). Methods: Genome-wide association study (GWAS) summarized data for hypotension and delirium were obtained from the FinnGen Consortium. The researchers utilized several statistical methods, such as inverse-variance weighted (IVW), weighted median, MR Egger, weighted mode, and simple mode in conducting the MR statistical analysis. In order to identify heterogeneity among the MR outcomes, we employed the Cochrane's Q test. Furthermore, we used the MR-Egger intercept test and MR pleiotropy residual sum and outliers (MR-PRESSO) test to examine horizontal pleiotropy. Results: The findings revealed that hypotension was identified as an independent hazard variable for delirium (p = 0.010, odds ratio [OR] [95% confidence interval (CI)] = 1.302 [1.066-1.592]) using the IVW method. The presence of horizontal pleiotropy was found to have minimal impact on establishing causal relationship (p = 0.999), and there was no evidence to suggest heterogeneity between genetic variations (p = 0.379). Additionally, the leave-one-out method demonstrated the stability and robustness of this association. Conclusion: We performed two-sample MR analyses and found evidence of a genetic causal relationship between hypotension and delirium. Our findings suggest that individuals with a genetic predisposition for hypotension may have a higher risk of developing delirium. This suggests that interventions aimed at improving perioperative hypotension could aid in limiting the incidence of delirium. [ABSTRACT FROM AUTHOR]

Background: Cerebral aneurysm is a high-risk cerebrovascular disease with a poor prognosis, potentially linked to multiple factors. This study aims to explore the association between mitochondrial-associated proteins and the risk of cerebral aneurysms using Mendelian randomization (MR) methods. Methods: We used GWAS summary statistics from the IEU Open GWAS project for mitochondrial-associated proteins and from the Finnish database for cerebral aneurysms (uIA, aSAH). The association between mitochondrial-associated exposures and cerebral aneurysms was evaluated using MR-Egger, weighted mode, IVW, simple mode and weighted median methods. Reverse MR assessed reverse causal relationship, while sensitivity analyses examined heterogeneity and pleiotropy in the instrumental variables. Significant causal relationship with cerebral aneurysms were confirmed using FDR correction. Results: Through MR analysis, we identified six mitochondrial proteins associated with an increased risk of aSAH: AIF1 (OR: 1.394, 95% CI: 1.109-1.752, p = 0.0044), CCDC90B (OR: 1.318, 95% CI: 1.132-1.535, p = 0.0004), TIM14 (OR: 1.272, 95% CI: 1.041-1.553, p = 0.0186), NAGS (OR: 1.219, 95% CI: 1.008-1.475, p = 0.041), tRNA PusA (OR: 1.311, 95% CI: 1.096-1.569, p = 0.003), and MRM3 (OR: 1.097, 95% CI: 1.016-1.185, p = 0.0175). Among these, CCDC90B, tRNA PusA, and AIF1 demonstrated a significant causal relationship with an increased risk of aSAH (FDR q < 0.1). Three mitochondrial proteins were associated with an increased risk of uIA: CCDC90B (OR: 1.309, 95% CI: 1.05-1.632, p = 0.0165), tRNA PusA (OR: 1.306, 95% CI: 1.007-1.694, p = 0.0438), and MRM3 (OR: 1.13, 95% CI: 1.012-1.263, p = 0.0303). In the reverse MR study, only one mitochondrial protein, TIM14 (OR: 1.087, 95% CI: 1.004-1.177, p = 0.04), showed a causal relationship with aSAH. Sensitivity analysis did not reveal heterogeneity or pleiotropy. The results suggest that CCDC90B, tRNA PusA, and MRM3 may be common risk factors for cerebral aneurysms (ruptured and unruptured), while AIF1 and NAGS are specifically associated with an increased risk of aSAH, unrelated to uIA. TIM14 may interact with aSAH. Conclusion: Our findings confirm a causal relationship between mitochondrialassociated proteins and cerebral aneurysms, offering new insights for future research into the pathogenesis and treatment of this condition. [ABSTRACT FROM AUTHOR]

Background: Micronutrient levels play a critical role in epilepsy. This study investigates the impact of micronutrient levels on epilepsy via Mendelian randomization (MR). Methods: A two-sample MR framework evaluated the genetic association between 15 serum micronutrients and epilepsy phenotypes. The analysis included calcium, iron, zinc, selenium, copper, magnesium, potassium, folate, vitamins B6, B12, C, D, E, retinol, and carotene against all epilepsy, generalized epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized tonic-clonic seizures alone and with spike-wave electroencephalography (GTCS), and various focal epilepsy phenotypes [with hippocampal sclerosis (HS), lesions other than HS, lesionnegative]. The random-effects inverse-variance weighted (IVW) model was the primary method used, supported by heterogeneity and pleiotropy assessments. Multivariable Mendelian randomization analyses (MVMR) were used to identify micronutrients that are significantly causally associated with different epilepsy subtypes and to confirm the most potential causal risk factors for these subtypes. Results: Zinc conferred an increased risk of focal epilepsy with HS (OR = 1.01; p = 0.045). Carotene was similarly linked to higher risks of lesion-negative cases (OR = 1.129; p = 0.037). Conversely, vitamin B6 was associated with reduced risks of focal epilepsy with HS (OR = 0.949; p = 0.020), and vitamin D was linked to decreased risks of both CAE (OR = 0.976, 95% CI: 0.959-0.993, p = 0.006) and JAE (OR = 0.986, 95% CI: 0.973-0.999, p = 0.032). These associations were robust, showing minimal heterogeneity and no evidence of pleiotropy across various sensitivity analyses. After adjustment using MVMR, significant causal relationships between vitamin D and both CAE and JAE remained. Furthermore, the causal relationship between zinc and vitamin B6 on focal epilepsy with HS became non-significant, while carotene shifted from a risk factor to a protective factor for focal epilepsy lesion-negative after adjusting for vitamin D. Conclusion: MR estimates provide robust evidence for the causal effects of vitamin D on reducing the risk of CAE, and JAE, which might provide alternative treatment strategies. [ABSTRACT FROM AUTHOR]

Aim: Diabetes mellitus (DM) may promote the occurrence of epilepsy through mechanisms, such as inflammation, immune imbalance, and cerebrovascular injury, caused by metabolic abnormalities. However, evidence for the effects of DM and blood glucose (BG) on the risk of epilepsy is limited. Herein, this study used the Mendelian randomization (MR) method to investigate the potential causal associations of DM and BG-related indexes with epilepsy. Methods: In this two-sample MR study, summary statistics data of the genome-wide association studies (GWASs) on exposures, including type 1 diabetes mellitus (T1DM), T2DM, fasting glucose, and glycated hemoglobin (HbAlc), were extracted from the MRC-Integrative Epidemiology Unit (MRC-IEU). The GWAS data on study outcomes, including epilepsy, focal epilepsy, and generalized epilepsy, were obtained from the FinnGen consortium. MR-Egger regression was used to examine horizontal pleiotropism of instrumental variables (IVs), and Cochran's Q statistics was used to quantify the heterogeneity. MR analysis methods including inverse variance weighted (IVW) tests, weighted median, and MR-Egger were utilized to investigate the causal associations between DM and BG-related indexes with epilepsy. The evaluation indexes were odds ratios (ORs) and 95% confidence intervals (CIs). Reverse causal association analyses were also performed. In addition, IVW-radial and leave-one-out tests were utilized for sensitivity analyses. Results: IVW estimates suggested that T1DM has potential causal associations with epilepsy (OR = 1.057, 95% CI: 1.031-1.084) and generalized epilepsy (OR = 1.066, 95% CI: 1.018-1.116). No significant reverse causal associations of T1DM with epilepsy or generalized epilepsy were found (all P > 0.05). In addition, sensitivity analysis results identified no outlier, indicating that the associations of T1DM with epilepsy and generalized epilepsy were relatively robust. Conclusion: Patients with T1DM had a potential risk of developing epilepsy, and prompt treatment of DM and dynamic monitoring may be beneficial to prevent epilepsy in this high-risk population. However, the causal associations of DM and BG with epilepsy may warrant further verification. [ABSTRACT FROM AUTHOR]

Background: Although observational studies have suggested a bidirectional relation between depression and intracranial aneurysms (IAs), their causal relations remain unclear. Thus we aimed to assess the causal association between depression and IAs. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from publicly available genome-wide association studies of depression (n = 500,199), IAs (n = 79,429), unruptured intracranial aneurysm (uIA) (n = 74,004), and subarachnoid hemorrhage (SAH) (n = 77,074). MR analyses included the inverse-variance weighted (IVW) method as the primary analytic, plus weighted-median, simple mode, weighted mode, MR-Egger, and MR PRESSO. Results: Genetically predicted depression was strongly positively related to IAs (odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.19-2.39, p = 0.003), uIA (OR = 1.96, 95% CI 1.06-3.64, p = 0.032), and SAH (OR = 1.73, 95% CI 1.14-2.61, p = 0.009). Reverse MR analyses showed that while genetically predicted uIA was positively related to depression (OR = 1.02, 95% CI 1.00-1.05, p = 0.044), no causal relations were observed for either IAs or SAH for depression. Conclusion: Our findings provide evidence of a causal effect of depression on IAs, uIA, and SAH. For the reverse MR analyses, we found a causal impact of uIA on depression, but no causal influence of either IAs or SAH for depression. [ABSTRACT FROM AUTHOR]

Objectives: This Mendelian randomization (MR) study identified modifiable risk factors for isolated rapid eye movement sleep behavior disorder (iRBD). Methods: Genome-wide association study (GWAS) datasets for 29 modifiable risk factors for iRBD in discovery and replication stages were used. GWAS data for iRBD cases were obtained from the International RBD Study Group. The inverse variance weighted (IVW) method was primarily employed to explore causality, with supplementary analyses used to verify the robustness of IVW findings. Co-localization analysis further substantiated causal associations identified via MR. Genetic correlations between mental illness and iRBD were identified using trait covariance, linkage disequilibrium score regression, and co-localization analyses. Results: Our study revealed causal associations between sun exposure-related factors and iRBD. Utilizing sun protection (odds ratio [OR] = 0.31 [0.14, 0.69], p = 0.004), ease of sunburn (OR = 0.70 [0.57, 0.87], p = 0.001), childhood sunburn occasions (OR = 0.58 [0.39, 0.87], p = 0.008), and phototoxic dermatitis (OR = 0.78 [0.66, 0.92], p = 0.003) decreased iRBD risk. Conversely, a deep skin color increased risk (OR = 1.42 [1.04, 1.93], p = 0.026). Smoking, alcohol consumption, low education levels, and mental illness were not risk factors for iRBD. Anxiety disorders and iRBD were genetically correlated. Conclusion: Our study does not corroborate previous findings that identified smoking, alcohol use, low education, and mental illness as risk factors for iRBD. Moreover, we found that excessive sun exposure elevates iRBD risk. These findings offer new insights for screening high-risk populations and devising preventive measures. [ABSTRACT FROM AUTHOR]

Background and objectives: As indicated by observational and genetic variation studies, age at first sexual intercourse (AFS) may be associated with migraine attack, but there is a lack of evidence from real-world studies due to ethical concerns. Therefore, we conducted a Mendelian randomization study to determine the causal relationship between AFS and migraine. Methods: We extracted instrumental variables from summary data of a genomewide association study (GWAS) on AFS and migraine and then conducted twosample Mendelian randomization analyses. GWAS data for AFS and migraine were obtained from 397,338 unrelated individuals (214,547 females and 182,791 males) and 306,314 individuals (18,477 patients and 287,837 control individuals), respectively. Results: There was a causal relationship between AFS and risk for migraine (odds ratio (OR) = 0.73, 95% confidence interval (CI) [0.61 to 0.86]), both for migraine with aura (MWA; OR = 0.72, 95% CI [0.58 to 0.89]) and migraine without aura (MOA; OR = 0.66, 95% CI [0.51 to 0.86]). Stratified analyses provided suggestive evidence of the causal relationship between delayed AFS and a decreased risk of migraine for both males (OR = 0.71, 95% CI [0.59 to 0.84]) and females (OR = 0.73, 95% CI [0.61 to 0.89]). Reverse Mendelian randomization did not reveal any effect of migraine on AFS (p > 0.05). No pleiotropy was detected. Discussion: A delayed AFS is a protective factor against migraine (for both MWA and MOA) in both males and females. This causal relationship indicates the presence of extracranial regulatory pathways of migraine. [ABSTRACT FROM AUTHOR]

Background: Previous epidemiological and other studies have shown an association between major depressive disorder (MDD) and migraine. However, the causal relationship between them remains unclear. Therefore, this study aimed to investigate the causal relationship between MDD and migraine using a bidirectional, two-sample Mendelian randomization (MR) approach. Methods: Data on MDD and migraine, including subtypes with aura migraine (MA) and without aura migraine (MO), were gathered from a publicly available genomewide association study (GWAS). Single nucleotide polymorphisms (SNPs) utilized as instrumental variables (IVs) were then screened by adjusting the intensity of the connection and removing linkage disequilibrium. To explore causal effects, inverse variance weighting (IVW) was used as the primary analysis method, with weighted median, MR-Egger, simple mode, and weighted mode used as supplementary analytic methods. Furthermore, heterogeneity and pleiotropy tests were carried out. Cochran's Q-test with IVW and MR-Egger was used to assess heterogeneity. Pleiotropy testing was carried out using the MR-Egger intercept and MR-PRESSO analysis methods. A leave-one-out analysis was also used to evaluate the stability of the findings. Finally, we used migraine (MA and MO) levels to deduce reverse causality with MDD risk. Results: Random effects IVW results were (MDD-Migraine: odds ratio (OR), 1.606, 95% confidence interval (CI), 1.324-1.949, p = 1.52E-06; MDD-MA: OR, 1.400, 95%CI, 1.067-1.8378, p = 0.015; MDD-MO: OR, 1.814, 95%CI, 1.277-2.578, p = 0.0008), indicating a causal relationship between MDD levels and increased risk of migraine (including MA and MO). In the inverse MR analysis, the findings were all negative, while in sensitivity analyses, the results were robust except for the study of MA with MDD. Conclusion: Our study confirms a causal relationship between MDD levels and increased risk of migraine, MA, and MO. There was little evidence in the reverse MR analysis to suggest a causal genetic relationship between migraine (MA and MO) and MDD risk levels. [ABSTRACT FROM AUTHOR]

BackgroundPrevious epidemiological and other studies have shown an association between ischemic stroke (IS) and frozen shoulder (FS). However, the causal relationship between them remains unclear. Therefore, the present study aimed to investigate the causal relationship between IS and FS using a two-sample Mendelian randomization method.MethodsOur research was divided into two stages: discovery and replication. The data were extracted from publicly available genome-wide association studies (GWAS). We selected a large sample of IS (n = 440, 328) and its subtypes (large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and stroke caused by small-vessel disease (SVS) and lacunar stroke (n = 254, 959) as exposure data. Additionally, we selected a large sample of FS as outcome data (n = 451, 099). Inverse variance weighting (IVW) was applied as the primary analysis method. The weighted median, MR-Egger, simple model, and weighted model were used as complementary analysis methods to assess causal effects. Moreover, heterogeneity was analyzed using Cochran's Q-test with IVW and MR-Egger. The MR-Egger intercept and MR-PRESSO analysis methods were used for pleiotropy testing. The stability of the results was also assessed using a leave-one-out analysis.ResultsIn the discovery stage, the IVW approach revealed an odds ratio (OR) of 1.207 with a 95% confidence interval (CI) of 1.027–1.417 and a P-value of 0.022. This suggests a causal association between IS levels and an increased risk of FS. In the subtype studies of IS, the findings were negative. However, during the replication stage, a significant causal link was found between selected lacunar strokes and FS with an OR of 1.252, a 95% CI of 1.105–1.419, and a P-value of 0.0004. All studies had no pleiotropy or heterogeneity, and the findings were robust.ConclusionsOur study confirmed the causal relationship between any IS level and increased risk of FS. Furthermore, the same results were obtained in the replication stage with lacunar stroke as an exposure factor. However, there was no direct causal relationship between the subtypes of IS and FS. Our study provides theoretical support for shoulder care for patients with IS.

Background: Multiple risk factors of stroke have been identified in previous studies; however, the causal role of snoring in the onset of stroke is less investigated. To clarify the causal association of snoring on stroke and its subtypes, this study is performed. Methods: The single nucleotide polymorphisms in relation to snoring were retrieved from the UK biobank cohort with 408,317 participants. The data for stroke and its subtypes of European ancestry (67,162 cases and 453,702 controls) were obtained fromtheMEGASTROKE consortium. In single-variable Mendelian randomization (SVMR) and multivariable MR (MVMR) analyses, inverse variance weighting was used as the primary estimate, complemented with sensitivity analyses more robust to pleiotropy. Results: Genetically predicted snoring increased the risk of stroke (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.19-6.08, P = 0.016) and ischemic stroke (IS) (OR = 2.82, 95% CI = 1.23-6.44, P = 0.013), but not large artery stroke (LAS) (OR = 3.02, 95% CI = 0.31-29.44, P = 0.339), cardioembolic stroke (CES) (OR = 1.51, 95% CI = 0.58-3.92, P = 0.395). We provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS. Conclusion: Our findings provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested that hearing impairment (HI) was associated with the risk of falls, but it remains unclear if this association is of causal nature. Methods: A two-sample Mendelian randomization (MR) study was conducted to investigate the causal association between HI and falls in individuals of European descent. Summary data on the association of single nucleotide polymorphisms (SNPs) with HI were obtained from the hitherto largest genome-wide association study (GWAS) (n = 323,978), and statistics on the association of SNPs with falls were extracted from another recently published GWAS (n = 461,725). MR Steiger filtering method was applied to determine the causal direction between HI and falls. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal association between HI and falls, whereas weighted median, simple mode, weighted mode, and MR-Egger methods were used as complementary analyses. The MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were performed to detect the potential directional pleiotropy and heterogeneity, respectively. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association. Results: A total of 18 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The positive causality between HI and risk of falls was indicated by IVW [OR 1.108 (95% CI 1.028, 1.194), p = 0.007]. The sensitivity analyses yielded comparable results. The "leave-one-out" analysis proved that lack of a single SNP did not affect the robustness of our results. The MR-Egger intercept test exhibited that genetic pleiotropy did not bias the results [intercept = −2.4E−04, SE = 0.001, p = 0.832]. Cochran's Q test revealed no heterogeneity. Conclusion: Our MR study revealed a causal association between genetically predicted HI and falls. These results provide further evidence supporting the need to effectively manage HI to minimize fall risks and improve quality of life. [ABSTRACT FROM AUTHOR]

BackgroundObservational studies have suggested that hearing impairment (HI) was associated with the risk of falls, but it remains unclear if this association is of causal nature.MethodsA two-sample Mendelian randomization (MR) study was conducted to investigate the causal association between HI and falls in individuals of European descent. Summary data on the association of single nucleotide polymorphisms (SNPs) with HI were obtained from the hitherto largest genome-wide association study (GWAS) (n = 323,978), and statistics on the association of SNPs with falls were extracted from another recently published GWAS (n = 461,725). MR Steiger filtering method was applied to determine the causal direction between HI and falls. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal association between HI and falls, whereas weighted median, simple mode, weighted mode, and MR-Egger methods were used as complementary analyses. The MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were performed to detect the potential directional pleiotropy and heterogeneity, respectively. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association.ResultsA total of 18 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The positive causality between HI and risk of falls was indicated by IVW [OR 1.108 (95% CI 1.028, 1.194), p = 0.007]. The sensitivity analyses yielded comparable results. The “leave-one-out” analysis proved that lack of a single SNP did not affect the robustness of our results. The MR-Egger intercept test exhibited that genetic pleiotropy did not bias the results [intercept = −2.4E−04, SE = 0.001, p = 0.832]. Cochran's Q test revealed no heterogeneity.ConclusionOur MR study revealed a causal association between genetically predicted HI and falls. These results provide further evidence supporting the need to effectively manage HI to minimize fall risks and improve quality of life.

Background: Cerebral aneurysm is a high-risk cerebrovascular disease with a poor prognosis, potentially linked to multiple factors. This study aims to explore the association between mitochondrial-associated proteins and the risk of cerebral aneurysms using Mendelian randomization (MR) methods., Methods: We used GWAS summary statistics from the IEU Open GWAS project for mitochondrial-associated proteins and from the Finnish database for cerebral aneurysms (uIA, aSAH). The association between mitochondrial-associated exposures and cerebral aneurysms was evaluated using MR-Egger, weighted mode, IVW, simple mode and weighted median methods. Reverse MR assessed reverse causal relationship, while sensitivity analyses examined heterogeneity and pleiotropy in the instrumental variables. Significant causal relationship with cerebral aneurysms were confirmed using FDR correction., Results: Through MR analysis, we identified six mitochondrial proteins associated with an increased risk of aSAH: AIF1 (OR: 1.394, 95% CI: 1.109-1.752, p  = 0.0044), CCDC90B (OR: 1.318, 95% CI: 1.132-1.535, p  = 0.0004), TIM14 (OR: 1.272, 95% CI: 1.041-1.553, p  = 0.0186), NAGS (OR: 1.219, 95% CI: 1.008-1.475, p  = 0.041), tRNA PusA (OR: 1.311, 95% CI: 1.096-1.569, p  = 0.003), and MRM3 (OR: 1.097, 95% CI: 1.016-1.185, p  = 0.0175). Among these, CCDC90B, tRNA PusA, and AIF1 demonstrated a significant causal relationship with an increased risk of aSAH (FDR q  < 0.1). Three mitochondrial proteins were associated with an increased risk of uIA: CCDC90B (OR: 1.309, 95% CI: 1.05-1.632, p  = 0.0165), tRNA PusA (OR: 1.306, 95% CI: 1.007-1.694, p  = 0.0438), and MRM3 (OR: 1.13, 95% CI: 1.012-1.263, p  = 0.0303). In the reverse MR study, only one mitochondrial protein, TIM14 (OR: 1.087, 95% CI: 1.004-1.177, p  = 0.04), showed a causal relationship with aSAH. Sensitivity analysis did not reveal heterogeneity or pleiotropy. The results suggest that CCDC90B, tRNA PusA, and MRM3 may be common risk factors for cerebral aneurysms (ruptured and unruptured), while AIF1 and NAGS are specifically associated with an increased risk of aSAH, unrelated to uIA. TIM14 may interact with aSAH., Conclusion: Our findings confirm a causal relationship between mitochondrial-associated proteins and cerebral aneurysms, offering new insights for future research into the pathogenesis and treatment of this condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Wang, Niu, Zhang, Yang, Hou and Lin.)

Background: Observational research suggests that hypotension is a potential hazard factor of delirium. Nevertheless, previous observational articles are limited in their ability to establish causality between hypotension and delirium. The present study was sought to explore the genetic causal relationship between these two conditions using two-sample Mendelian randomization (MR)., Methods: Genome-wide association study (GWAS) summarized data for hypotension and delirium were obtained from the FinnGen Consortium. The researchers utilized several statistical methods, such as inverse-variance weighted (IVW), weighted median, MR Egger, weighted mode, and simple mode in conducting the MR statistical analysis. In order to identify heterogeneity among the MR outcomes, we employed the Cochrane's Q test. Furthermore, we used the MR-Egger intercept test and MR pleiotropy residual sum and outliers (MR-PRESSO) test to examine horizontal pleiotropy., Results: The findings revealed that hypotension was identified as an independent hazard variable for delirium ( p  = 0.010, odds ratio [OR] [95% confidence interval (CI)] = 1.302 [1.066-1.592]) using the IVW method. The presence of horizontal pleiotropy was found to have minimal impact on establishing causal relationship ( p  = 0.999), and there was no evidence to suggest heterogeneity between genetic variations ( p  = 0.379). Additionally, the leave-one-out method demonstrated the stability and robustness of this association., Conclusion: We performed two-sample MR analyses and found evidence of a genetic causal relationship between hypotension and delirium. Our findings suggest that individuals with a genetic predisposition for hypotension may have a higher risk of developing delirium. This suggests that interventions aimed at improving perioperative hypotension could aid in limiting the incidence of delirium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Wu, Lin, Liu, Liufu and Cao.)

Background: Micronutrient levels play a critical role in epilepsy. This study investigates the impact of micronutrient levels on epilepsy via Mendelian randomization (MR)., Methods: A two-sample MR framework evaluated the genetic association between 15 serum micronutrients and epilepsy phenotypes. The analysis included calcium, iron, zinc, selenium, copper, magnesium, potassium, folate, vitamins B6, B12, C, D, E, retinol, and carotene against all epilepsy, generalized epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized tonic-clonic seizures alone and with spike-wave electroencephalography (GTCS), and various focal epilepsy phenotypes [with hippocampal sclerosis (HS), lesions other than HS, lesion-negative]. The random-effects inverse-variance weighted (IVW) model was the primary method used, supported by heterogeneity and pleiotropy assessments. Multivariable Mendelian randomization analyses (MVMR) were used to identify micronutrients that are significantly causally associated with different epilepsy subtypes and to confirm the most potential causal risk factors for these subtypes., Results: Zinc conferred an increased risk of focal epilepsy with HS (OR = 1.01; p  = 0.045). Carotene was similarly linked to higher risks of lesion-negative cases (OR = 1.129; p  = 0.037). Conversely, vitamin B6 was associated with reduced risks of focal epilepsy with HS (OR = 0.949; p  = 0.020), and vitamin D was linked to decreased risks of both CAE (OR = 0.976, 95% CI: 0.959-0.993, p  = 0.006) and JAE (OR = 0.986, 95% CI: 0.973-0.999, p  = 0.032). These associations were robust, showing minimal heterogeneity and no evidence of pleiotropy across various sensitivity analyses. After adjustment using MVMR, significant causal relationships between vitamin D and both CAE and JAE remained. Furthermore, the causal relationship between zinc and vitamin B6 on focal epilepsy with HS became non-significant, while carotene shifted from a risk factor to a protective factor for focal epilepsy lesion-negative after adjusting for vitamin D., Conclusion: MR estimates provide robust evidence for the causal effects of vitamin D on reducing the risk of CAE, and JAE, which might provide alternative treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Zheng, Cai and Gao.)

Aim: Diabetes mellitus (DM) may promote the occurrence of epilepsy through mechanisms, such as inflammation, immune imbalance, and cerebrovascular injury, caused by metabolic abnormalities. However, evidence for the effects of DM and blood glucose (BG) on the risk of epilepsy is limited. Herein, this study used the Mendelian randomization (MR) method to investigate the potential causal associations of DM and BG-related indexes with epilepsy., Methods: In this two-sample MR study, summary statistics data of the genome-wide association studies (GWASs) on exposures, including type 1 diabetes mellitus (T1DM), T2DM, fasting glucose, and glycated hemoglobin (HbAlc), were extracted from the MRC-Integrative Epidemiology Unit (MRC-IEU). The GWAS data on study outcomes, including epilepsy, focal epilepsy, and generalized epilepsy, were obtained from the FinnGen consortium. MR-Egger regression was used to examine horizontal pleiotropism of instrumental variables (IVs), and Cochran's Q statistics was used to quantify the heterogeneity. MR analysis methods including inverse variance weighted (IVW) tests, weighted median, and MR-Egger were utilized to investigate the causal associations between DM and BG-related indexes with epilepsy. The evaluation indexes were odds ratios (ORs) and 95% confidence intervals (CIs). Reverse causal association analyses were also performed. In addition, IVW-radial and leave-one-out tests were utilized for sensitivity analyses., Results: IVW estimates suggested that T1DM has potential causal associations with epilepsy (OR = 1.057, 95% CI: 1.031-1.084) and generalized epilepsy (OR = 1.066, 95% CI: 1.018-1.116). No significant reverse causal associations of T1DM with epilepsy or generalized epilepsy were found (all P > 0.05). In addition, sensitivity analysis results identified no outlier, indicating that the associations of T1DM with epilepsy and generalized epilepsy were relatively robust., Conclusion: Patients with T1DM had a potential risk of developing epilepsy, and prompt treatment of DM and dynamic monitoring may be beneficial to prevent epilepsy in this high-risk population. However, the causal associations of DM and BG with epilepsy may warrant further verification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu and Ling.)

Background: Although observational studies have suggested a bidirectional relation between depression and intracranial aneurysms (IAs), their causal relations remain unclear. Thus we aimed to assess the causal association between depression and IAs., Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from publicly available genome-wide association studies of depression ( n  = 500,199), IAs ( n  = 79,429), unruptured intracranial aneurysm (uIA) ( n  = 74,004), and subarachnoid hemorrhage (SAH) ( n  = 77,074). MR analyses included the inverse-variance weighted (IVW) method as the primary analytic, plus weighted-median, simple mode, weighted mode, MR-Egger, and MR PRESSO., Results: Genetically predicted depression was strongly positively related to IAs (odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.19-2.39, p  = 0.003), uIA (OR = 1.96, 95% CI 1.06-3.64, p  = 0.032), and SAH (OR = 1.73, 95% CI 1.14-2.61, p  = 0.009). Reverse MR analyses showed that while genetically predicted uIA was positively related to depression (OR = 1.02, 95% CI 1.00-1.05, p  = 0.044), no causal relations were observed for either IAs or SAH for depression., Conclusion: Our findings provide evidence of a causal effect of depression on IAs, uIA, and SAH. For the reverse MR analyses, we found a causal impact of uIA on depression, but no causal influence of either IAs or SAH for depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Sun and Ma.)

Objectives: This Mendelian randomization (MR) study identified modifiable risk factors for isolated rapid eye movement sleep behavior disorder (iRBD)., Methods: Genome-wide association study (GWAS) datasets for 29 modifiable risk factors for iRBD in discovery and replication stages were used. GWAS data for iRBD cases were obtained from the International RBD Study Group. The inverse variance weighted (IVW) method was primarily employed to explore causality, with supplementary analyses used to verify the robustness of IVW findings. Co-localization analysis further substantiated causal associations identified via MR. Genetic correlations between mental illness and iRBD were identified using trait covariance, linkage disequilibrium score regression, and co-localization analyses., Results: Our study revealed causal associations between sun exposure-related factors and iRBD. Utilizing sun protection (odds ratio [OR] = 0.31 [0.14, 0.69], p  = 0.004), ease of sunburn (OR = 0.70 [0.57, 0.87], p  = 0.001), childhood sunburn occasions (OR = 0.58 [0.39, 0.87], p  = 0.008), and phototoxic dermatitis (OR = 0.78 [0.66, 0.92], p  = 0.003) decreased iRBD risk. Conversely, a deep skin color increased risk (OR = 1.42 [1.04, 1.93], p  = 0.026). Smoking, alcohol consumption, low education levels, and mental illness were not risk factors for iRBD. Anxiety disorders and iRBD were genetically correlated., Conclusion: Our study does not corroborate previous findings that identified smoking, alcohol use, low education, and mental illness as risk factors for iRBD. Moreover, we found that excessive sun exposure elevates iRBD risk. These findings offer new insights for screening high-risk populations and devising preventive measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Li, Zhang, Xin, Huang and Zhao.)

Background and Objectives: As indicated by observational and genetic variation studies, age at first sexual intercourse (AFS) may be associated with migraine attack, but there is a lack of evidence from real-world studies due to ethical concerns. Therefore, we conducted a Mendelian randomization study to determine the causal relationship between AFS and migraine., Methods: We extracted instrumental variables from summary data of a genome-wide association study (GWAS) on AFS and migraine and then conducted two-sample Mendelian randomization analyses. GWAS data for AFS and migraine were obtained from 397,338 unrelated individuals (214,547 females and 182,791 males) and 306,314 individuals (18,477 patients and 287,837 control individuals), respectively., Results: There was a causal relationship between AFS and risk for migraine (odds ratio (OR) = 0.73, 95% confidence interval (CI) [0.61 to 0.86]), both for migraine with aura (MWA; OR = 0.72, 95% CI [0.58 to 0.89]) and migraine without aura (MOA; OR = 0.66, 95% CI [0.51 to 0.86]). Stratified analyses provided suggestive evidence of the causal relationship between delayed AFS and a decreased risk of migraine for both males (OR = 0.71, 95% CI [0.59 to 0.84]) and females (OR = 0.73, 95% CI [0.61 to 0.89]). Reverse Mendelian randomization did not reveal any effect of migraine on AFS ( p  > 0.05). No pleiotropy was detected., Discussion: A delayed AFS is a protective factor against migraine (for both MWA and MOA) in both males and females. This causal relationship indicates the presence of extracranial regulatory pathways of migraine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Wang, Wang and Kong.)

Background: Previous epidemiological and other studies have shown an association between ischemic stroke (IS) and frozen shoulder (FS). However, the causal relationship between them remains unclear. Therefore, the present study aimed to investigate the causal relationship between IS and FS using a two-sample Mendelian randomization method., Methods: Our research was divided into two stages: discovery and replication. The data were extracted from publicly available genome-wide association studies (GWAS). We selected a large sample of IS ( n = 440, 328) and its subtypes (large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and stroke caused by small-vessel disease (SVS) and lacunar stroke ( n = 254, 959) as exposure data. Additionally, we selected a large sample of FS as outcome data ( n = 451, 099). Inverse variance weighting (IVW) was applied as the primary analysis method. The weighted median, MR-Egger, simple model, and weighted model were used as complementary analysis methods to assess causal effects. Moreover, heterogeneity was analyzed using Cochran's Q-test with IVW and MR-Egger. The MR-Egger intercept and MR-PRESSO analysis methods were used for pleiotropy testing. The stability of the results was also assessed using a leave-one-out analysis., Results: In the discovery stage, the IVW approach revealed an odds ratio (OR) of 1.207 with a 95% confidence interval (CI) of 1.027-1.417 and a P -value of 0.022. This suggests a causal association between IS levels and an increased risk of FS. In the subtype studies of IS, the findings were negative. However, during the replication stage, a significant causal link was found between selected lacunar strokes and FS with an OR of 1.252, a 95% CI of 1.105-1.419, and a P -value of 0.0004. All studies had no pleiotropy or heterogeneity, and the findings were robust., Conclusions: Our study confirmed the causal relationship between any IS level and increased risk of FS. Furthermore, the same results were obtained in the replication stage with lacunar stroke as an exposure factor. However, there was no direct causal relationship between the subtypes of IS and FS. Our study provides theoretical support for shoulder care for patients with IS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lv, Hu, Liang, Liu, Gong, Du, Deng, Qian, Nie and Luo.)

Background: Previous epidemiological and other studies have shown an association between major depressive disorder (MDD) and migraine. However, the causal relationship between them remains unclear. Therefore, this study aimed to investigate the causal relationship between MDD and migraine using a bidirectional, two-sample Mendelian randomization (MR) approach., Methods: Data on MDD and migraine, including subtypes with aura migraine (MA) and without aura migraine (MO), were gathered from a publicly available genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) utilized as instrumental variables (IVs) were then screened by adjusting the intensity of the connection and removing linkage disequilibrium. To explore causal effects, inverse variance weighting (IVW) was used as the primary analysis method, with weighted median, MR-Egger, simple mode, and weighted mode used as supplementary analytic methods. Furthermore, heterogeneity and pleiotropy tests were carried out. Cochran's Q-test with IVW and MR-Egger was used to assess heterogeneity. Pleiotropy testing was carried out using the MR-Egger intercept and MR-PRESSO analysis methods. A leave-one-out analysis was also used to evaluate the stability of the findings. Finally, we used migraine (MA and MO) levels to deduce reverse causality with MDD risk., Results: Random effects IVW results were (MDD-Migraine: odds ratio (OR), 1.606, 95% confidence interval (CI), 1.324-1.949, p = 1.52E-06; MDD-MA: OR, 1.400, 95%CI, 1.067-1.8378, p = 0.015; MDD-MO: OR, 1.814, 95%CI, 1.277-2.578, p = 0.0008), indicating a causal relationship between MDD levels and increased risk of migraine (including MA and MO). In the inverse MR analysis, the findings were all negative, while in sensitivity analyses, the results were robust except for the study of MA with MDD., Conclusion: Our study confirms a causal relationship between MDD levels and increased risk of migraine, MA, and MO. There was little evidence in the reverse MR analysis to suggest a causal genetic relationship between migraine (MA and MO) and MDD risk levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lv, Xu, Tang, Liu, Qian, Guo and Luo.)

Background: Multiple risk factors of stroke have been identified in previous studies; however, the causal role of snoring in the onset of stroke is less investigated. To clarify the causal association of snoring on stroke and its subtypes, this study is performed., Methods: The single nucleotide polymorphisms in relation to snoring were retrieved from the UK biobank cohort with 408,317 participants. The data for stroke and its subtypes of European ancestry (67,162 cases and 453,702 controls) were obtained from the MEGASTROKE consortium. In single-variable Mendelian randomization (SVMR) and multivariable MR (MVMR) analyses, inverse variance weighting was used as the primary estimate, complemented with sensitivity analyses more robust to pleiotropy., Results: Genetically predicted snoring increased the risk of stroke (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.19-6.08, P = 0.016) and ischemic stroke (IS) (OR = 2.82, 95% CI = 1.23-6.44, P = 0.013), but not large artery stroke (LAS) (OR = 3.02, 95% CI = 0.31-29.44, P = 0.339), cardioembolic stroke (CES) (OR = 1.51, 95% CI = 0.58-3.92, P = 0.395). We provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS., Conclusion: Our findings provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Ren, Li, Wang, Tao, Ma and You.)