BACKGROUND: While growing evidence suggests a relationship between migraine and cardiovascular disease, the genetic evidence for a causal relationship between migraine and cardiovascular disease is still scarce. Investigating the causal association between migraine and cardiovascular disease is vital.
METHODS: We carried out a bidirectional Mendelian randomization (MR) study including discovery samples and replication samples using publicly available genome-wide association study (GWAS) summary datasets and stringent screening instrumental variables. Four different MR techniques-Inverse variance weighted (IVW), MR ‒Egger, weighted median, and weighted mode-as well as various sensitivity analyses-Cochran\'s Q, IVW radial, leave-one-out (LOO), and MR-PRESSO-were utilized to investigate the causal relationship between cardiovascular disease and migraine.
RESULTS: The protective causal effects of genetically predicted migraine on coronary artery disease (OR, 0.881; 95% CI 0.790-0.982; p = 0.023) and ischemic stroke (OR, 0.912; 95% CI 0.854-0.974; p = 0.006) were detected in forward MR analysis but not in any other cardiovascular disease. Consistently, we also discovered protective causal effects of coronary atherosclerosis (OR, 0.865; 95% CI 0.797-0.940; p = 0.001) and myocardial infarction (OR, 0.798; 95% CI 0.668-0.952; p = 0.012) on migraine in reverse MR analysis.
CONCLUSIONS: We found a potential protective effect of migraine on coronary artery disease and ischemic stroke and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine. We emphasised epidemiological and genetic differences and the need for long-term safety monitoring of migraine medications and future research to improve cardiovascular outcomes in migraine patients.

Osteoarthritis (OA) is a common degenerative disease that affects millions of individuals worldwide.
OBJECTIVE: There is no conclusive epidemiological evidence regarding the relationship between OA, depression, and whole-body fat mass. In this study, we conducted a two-step Mendelian randomization analysis to determine the causal relationships between them.
METHODS: The published summary-level data are from genome-wide association studies (GWAS). Our study included 357,957 samples and 10,828,862 SNPs. Finally, the outcome GWAS data for OA came from a GWAS on the genetic architecture of OA using UK Biobank data. This study included 50,508 samples and 15,845,511 SNPs. We used five different modes of analysis, including inverse variance weighted meta-analysis (IVW), MR-Egger regression, weighted median, simple mode, and weighted mode, to explore causal relationships.
RESULTS: We found a positive correlation between depression and body fat mass, with depression leading to body fat mass an increase in (IVW result: p = 3.39E-07, OR (95 % CI) =2.16 (1.61, 2.90)). We also found a positive correlation between body fat mass and OA, with body fat mass increasing the risk of OA (IVW result: p = 1.65E-33, OR (95 % CI) = 1.98 (1.77, 2.21). Body fat mass played an important role as a mediator in the causal relationship between depression and OA, with approximately 14 % of the risk of OA caused by depression being mediated by body fat mass.
CONCLUSIONS: Our study offers reliable evidence that depression has a detrimental impact on the risk of OA. Future research can support these associations from improving depressed effect, including social, biological, and behavioral factors, to reduce the risk of chronic diseases such as osteoarthritis. And we identified high-risk variation of alleles which associated with OA and depression can be used to predict disease and provide a basis for clinical intervention and treatment of OA.

UNASSIGNED: There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer\'s disease (AD). However, it is unclear whether the two are causally related.
UNASSIGNED: To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis.
UNASSIGNED: Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR-Egger regression, weighted median, simple mode, and weighted mode were applied to assess the pathogenic associations between the two diseases, and sensitivity analyses were used to further validate the robustness of the results.
UNASSIGNED: The results of forward MR analysis with T2DM as the exposure were [OR = 0.998, 95% CI (0.975∼1.021), p = 0.857], and the results of reverse MR analysis with AD as the exposure were [OR = 0.966, 95% CI (0.934∼0.999), p = 0.043]. The results showed no significant association between T2DM and AD at the gene level (p < 0.025). Sensitivity analyses were consistent with the results of the main analysis, confirming the robustness of the study.
UNASSIGNED: T2DM and AD may not be genetically causally associated.

UNASSIGNED: Observational studies have reported an association between body mass index (BMI) as well as height and the risk of pneumothorax. However, it has long been unclear whether BMI or height are causally associated with pneumothorax.
UNASSIGNED: Genetic summary data for BMI, height and pneumothorax were retrieved from multiple independent large genome-wide association studies (GWAS). A series of quality control steps were conducted to select instruments. Four independent two-sample Mendelian randomization (MR) analyzes were performed to adequately assess the causal relationship between BMI or height on pneumothorax, and the robustness of the results was assessed by a series of sensitivity analyzes.
UNASSIGNED: Height increased the risk of pneumothorax with an OR of 1.5181 (95%CI 1.3092-1.7604; p = 3.28e-08); there was no evidence of a causal effect of BMI on the risk of pneumothorax with an OR of 0.8979 (95%CI 0.7417-1.0869; p = 0.269). Height increased the risk of spontaneous pneumothorax with an OR of 1.0010 (95%CI 1.0002-1.0018; p = 0.012); the results showed no significant causal relationship between BMI and spontaneous pneumothorax either with an OR of 0.9992 (95%CI 0.9983-1.0002; p = 0.112).
UNASSIGNED: Our results supported a genetic association between height and pneumothorax. We found that height increased the risk of pneumothorax. However, no evidence was found to suggest a causal relationship between BMI and pneumothorax risk. The relationship between BMI and pneumothorax requires further in-depth analysis.

BACKGROUND: The aim of this study was to explore the causal association between immune cells and VaD based on a two-sample bidirectional Mendelian randomization study.
METHODS: Bidirectional two-sample MR analyses based on pooled datasets from publicly available genome-wide association studies were performed using inverse variance weighted (IVW), weighted median (WE), and MR-Egger regressions to evaluate the causal relationships between immune cells and vascular dementia. Heterogeneity was assessed using Cochran\'s Q statistic. The reliability of the MR analysis results was verified by using the MR-PRESSO method for outlier detection, the MR-Egger method for horizontal multivariate analysis, and the leave-one-out method for sensitivity analysis.
RESULTS: Specifically, 27 immunophenotypes were associated with VaD pathogenesis, including Sw mem %lymphocyte (P = 0.043), CD38 on CD20- (P = 0.039), CD11c+ monocyte AC (P = 0.024), DC AC (P = 0.002), CCR2 on CD62L+ myeloid DC (P = 0.039), Resting Treg %CD4 (P = 0.042), Activated & resting Treg %CD4+ (P = 0.038), CD28+ CD45RA- CD8br %CD8br (P = 0.047), NK %CD3- lymphocyte (P = 0.042), CD45 on B cell (P = 0.029), FSC-A on NKT (P = 0.033), CD45 on CD33br HLA DR+ CD14- (P = 0.039) were significantly correlated with increased VaD risk. Additionally, four immune phenotypes, namely, CD19 on CD20-, Resting Treg %CD4, Activated & resting Treg %CD4+, and CD11c+ monocyte AC, showed bidirectional effects on VaD.
CONCLUSIONS: MR analysis revealed potential causal relationships between certain immune cells and VaD. Our preliminary exploration through immune cell infiltration analysis highlights the significant value of immune cells in VaD. Therefore, this study may provide a new perspective for the prevention and treatment of VaD.

UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

BACKGROUND: Evidence suggests that coronavirus disease 2019 (COVID-19) is associated with the risk of cardiovascular diseases (CVDs). However, the results are inconsistent, and the causality remains to be established. We aimed to investigate the potential causal relationship between COVID-19 and CVDs by using two-sample Mendelian randomization (MR) analysis.
METHODS: Summary-level data for COVID-19 and CVDs including myocarditis, heart failure (HF), acute myocardial infarction (AMI), arrhythmia and venous thromboembolism (VTE) were obtained from the IEU OpenGWAS project, a public genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) were used as instrumental variables. Five complementary MR methods were performed, including inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode and simple mode methods. IVW method was considered as the primary approach. Besides, sensitivity analyses, including Cochran\'s Q test, MR-Egger intercept test, and leave-one-out analysis, were performed to evaluate the robustness of the results.
RESULTS: According to the IVW results, our MR study indicated that genetically predicted COVID-19 was not causally connected with the risk of CVDs [myocarditis: odds ratio (OR) = 1.407, 95% confidence interval (CI) = 0.761-2.602, p-value = 0.277; HF: OR = 1.180, 95% CI = 0.980-1.420, p-value = 0.080; AMI: OR = 1.002, 95% CI = 0.998-1.005, p-value = 0.241; arrhythmia: OR = 0.865, 95% CI = 0.717-1.044, p-value = 0.132; VTE: OR = 1.013, 95% CI = 0.997-1.028, p-value = 0.115]. The supplementary MR methods showed similar results. Sensitivity analyses suggested that the causal estimates were robust.
CONCLUSIONS: This two-sample MR analysis did not provide sufficient evidence for a causal relationship between COVID-19 and the risk of acute CVDs, which may provide new insights into the prevention of acute CVDs in COVID-19 patients.

Prior studies suggested that vitamin E might be beneficial in alleviating atopic dermatitis, but confirming a causal link was hindered by limitations such as sample sizes and unaccounted confounders. The present study aimed to clarify this through Mendelian randomization (MR) analysis. GWAS summary statistics was obtained from public databases encompassing a study on vitamin E and two studies related to atopic dermatitis. Two sets of instrumental variables (IVs) were selected using lenient (p < 1e-5) and strict (p < 5e-6) thresholds for separate MR analyses. Inverse variance weighted (IVW) was used as the primary MR method, supplemented by six additional MR methods, and followed by a meta-analysis to consolidate the impact of vitamin E on atopic dermatitis from two independent studies. Furthermore, various sensitivity tests were performed to assess the reliability of the MR results. A meta-analysis of IVW analyses deriving from two different atopic dermatitis cohorts under lenient IV selection thresholds demonstrated that vitamin E exhibited a significant lowering risk of atopic dermatitis effect (OR = 0.817, 95% CI: 0.673-0.991, p = .041), which was validated under strict IV selection thresholds (OR = 0.822, 95% CI: 0.709-0.954, p = .010). In addition, six other MR methods remained parallel to IVW (OR > 1). Multiple sensitivity tests showed that MR analyses were not affected by heterogeneity and horizontal pleiotropy. Overall, this MR study supported vitamin E reducing the risk of atopic dermatitis. Consequently, maintaining an adequate intake of vitamin E could potentially serve as an effective preventive measure against atopic dermatitis.

UNASSIGNED: Uveitis, characterized by inflammation of the iris, ciliary body, and choroid, presents a significant global clinical challenge, contributing substantially to visual impairment. Risk factors include autoimmune diseases and immune cell dysfunctions, yet many remain unidentified. Immune cells, notably T cells, B cells, and monocytes, play pivotal roles in uveitis pathogenesis. While biologic agents show promise, comprehensive studies on immune cell types in ocular diseases are lacking. Genome-wide association studies (GWAS) and Mendelian randomization (MR) present promising avenues to elucidate genetic susceptibilities and causal relationships between immune cell traits and uveitis risk.
UNASSIGNED: Two-sample MR analysis was used to evaluate the causal relationship between 731 immune cells and uveitis, and genome-wide significance analysis was performed for genetic variation in 731 immune cells traits (P < 5 × 10-8). Immune characteristics include median fluorescence intensity (MFI), relative cell counts (RC), absolute cell counts (AC), and morphological parameters (MP), which were determined by published GWAS, and public data from the IEU Open GWAS database. The main analysis method of MR is inverse variance weighting (IVW). Heterogeneity and horizontal pleiotropy were also assessed.
UNASSIGNED: 5 immunophenotypes, including CD62L-DC %DC, IgD+ CD38dim %B cell, CD3 on CM CD4+T cell, CD3 on CD45RA-CD4 +T cell, and CD3 on CD39+ CD4+ Treg may increase the risk of uveitis. 5 immunophenotypes, including CD11b on CD33dim HLA DR-Myeloid cell, HLA DR on CD33dim HLA DR+ CD11b-myeloid cell, CD14-CD16 + %monocyte, HLA DR on CD14-CD16 + monocyte and PDL-1 on CD14-CD16 + monocyte was negatively associated with the risk of uveitis. Among them, HLA DR on CD14-CD16 + monocyte (OR=0.921, 95%CI =0.875-0.970, P=0.001) and HLA DR on CD33dim HLA DR+ CD11b- (OR=0.879, 95%CI = 0.833-0.927, P=0.00) were negatively associated with the risk of uveitis in bi-direction.
UNASSIGNED: These results indicate that 10 immune cells traits are significantly associated with the risk of developing uveitis and 2 of them were strongly associated with uveitis bi-directionally, after excluding the effects of confounding factors such as some immune diseases, which provided new ideas and therapeutic targets for the study of immune mechanism of uveitis.