Bridging the gap: exploring the causal relationship between metformin and tumors.

Objective: Numerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis. Results: MR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae. Conclusion: Metformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings.

Genetically predicted immune cells mediate the association between gut microbiota and neuropathy pain.

BACKGROUND: Previous observational studies have indicated a complex association between gut microbiota (GM) and neuropathic pain (NP). Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between GM and neuropathic pain including post-herpetic neuralgia (PHN), painful diabetic peripheral neuropathy (PDPN), and trigeminal neuralgia (TN), as well as to explore the potential mediation effects of immune cells. METHODS: We performed a two-step, two-sample Mendelian randomization study with an inverse variance-weighted (IVW) approach to investigate the causal role of GM on three major kinds of NP and the mediation effect of immune cells between the association of GM and NP. In addition, we determine the strongest causal associations using Bayesian weighted Mendelian randomization (BWMR) analysis. Furthermore, we will investigate the mediating role of immune cells through a two-step Mendelian randomization design. RESULTS: We identified 53 taxonomies and pathways of gut microbiota that had significant causal associations with NP. In addition, we also discovered 120 immune cells that exhibited significant causal associations with NP. According to the BWMR and two-step Mendelian randomization analysis, we identified the following results CD4 on CM CD4 + (maturation stages of T cell) mediated 6.7% of the risk reduction for PHN through the pathway of fucose degradation (FUCCAT.PWY). CD28 + DN (CD4-CD8-) AC (Treg) mediated 12.5% of the risk reduction for PHN through the influence on Roseburia inulinivorans. CD45 on lymphocyte (Myeloid cell) mediated 11.9% of the risk increase for TN through the superpathway of acetyl-CoA biosynthesis (PWY.5173). HLA DR + CD8br %T cell (TBNK) mediated 3.2% of the risk reduction for TN through the superpathway of GDP-mannose-derived O-antigen building blocks biosynthesis (PWY.7323). IgD-CD38-AC (B cell) mediated 7.5% of the risk reduction for DPN through the pathway of thiazole biosynthesis I in E. coli (PWY.6892). DISCUSSION: These findings provided evidence supporting the causal effect of GM with NP, with immune cells playing a mediating role. These findings may inform prevention strategies and interventions directed toward NP. Future studies should explore other plausible biological mechanisms.

Genetic evidence for a causal link between gut microbiota and arterial embolism and thrombosis: a two-sample Mendelian randomization study.

Background: Previous research has hinted at a crucial link between gut microbiota and arterial embolism and thrombosis, yet the causal relationship remains enigmatic. To gain a deeper understanding, we aimed to comprehensively explore the causal relationship and elucidate the impact of the gut microbiota on the risk through a two-sample Mendelian randomization (MR) study. Methods: Genetic instrumental variables for gut microbiota were identified from a genome-wide association study (GWAS) of 18,340 participants. Summary statistics for IBS were drawn from a GWAS including 1,076 cases and 381,997 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the weighted median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Results: We identified three bacterial traits that were associated with the risk of arterial embolism and thrombosis: odds ratio (OR): 1.58, 95% confidence interval (CI): 1.08-2.31, p = 0.017 for genus Catenibacterium; OR: 0.64, 95% CI: 0.42-0.96, p = 0.031 for genus Dialister; and OR: 2.08, 95% CI: 1.25-3.47, p = 0.005 for genus Odoribacter. The results of sensitivity analyses for these bacterial traits were consistent (P<0.05). Conclusion: Our systematic analyses provided evidence to support a potential causal relationship between several gut microbiota taxa and the risk of arterial embolism and thrombosis. More studies are required to show how the gut microbiota affects the development of arterial embolism and thrombosis.

The causal relationship between smoking, alcohol consumption, and renal clear cell carcinoma: a Mendelian randomization study.

Introduction: Observational studies have found a correlation between the consumption of tobacco and alcohol and the likelihood of developing renal cell carcinoma. However, whether these associations indicate causal relationships is unclear. Methods: To establish if these connections indicate causal relationships, we performed a Mendelian Randomization (MR) analysis using a two-sample approach. For the number of daily cigarettes, lifetime smoking index, smoking initiation, and weekly drinking, we employed 44, 108, 174, and 76 single nucleotide polymorphisms (SNPs) as instrumental variables. Outcome data were obtained from the FinnGen Alliance, which included a combined total of 429,290 individuals. The MR analysis was conducted using the inverse-variance weighted (IVW) method to estimate causal effects. To address potential violations of MR assumptions due to directional pleiotropy, we performed MR-Egger regression and MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) analysis. Results: Genetically influenced smoking initiation was directly associated with the risk of developing renal cell carcinoma (OR = 1.55, 95% CI: 1.04-2.33; p = 0.03). No causal relationship was found between daily cigarette consumption and lifetime smoking index with the risk of renal cell cancer. Genetic predisposition for weekly alcohol consumption showed a reduced risk of renal cell cancer (OR = 0.45, 95% CI: 0.26-0.81; p = 0.007). Discussion: Our study suggests a potential causal relationship between alcohol consumption and reduced risk of renal cell cancer, while no such association was observed with smoking. Further research is needed to confirm these findings.

Relationship between Sjogren's syndrome and gastroesophageal reflux: A bidirectional Mendelian randomization study.

The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MR‒Egger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312-1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651-1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.

A bidirectional two-sample Mendelian randomization study to evaluate the relationship between psoriasis and interstitial lung diseases.

BACKGROUND: Prior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD. METHODS: Data regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms- MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode- to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method. RESULTS: The analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes. CONCLUSION: Our findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD.

T2DM may exert a protective effect against digestive system tumors in East Asian populations: a Mendelian randomization analysis.

Introduction: Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods to clarify its causal relationship and mechanisms. Five common digestive system tumors and four diabetes-related phenotypes were included. Methods: Inverse variance weighted method was the main analytical method. Meta-analysis was used to summarize results of multiple data sources. Horizontal pleiotropy was tested using Egger-intercept method and validated by MRPRESSO method. Heterogeneity and sensitivity analysis were conducted by Cochran's Q test and leave-one-out method, respectively. Results: T2DM is associated with a reduced risk of esophageal (OR: 0.77, 95% CI: 0.71 to 0.83, P< 0.001), gastric (OR: 0.87, 95% CI: 0.84 to 0.90, P< 0.001) and colorectal cancer (OR: 0.88, 95% CI: 0.85 to 0.91, P< 0.001) and hepatocellular carcinoma (OR: 0.92, 95% CI: 0.86 to 0.97, P = 0.005) and an increased risk of pancreatic cancer (OR: 1.92, 95% CI: 1.47 to 2.50, P< 0.001) in East Asian population. T2DM causes decreased fasting insulin levels (OR = 0.966, 95% CI: 0.95 to 0.98, P< 0.001) and increased glycated hemoglobin levels (OR=1.41, 95% CI: 1.39 to 1.44, P<0.001). Elevated fasting insulin levels increase the risk of esophageal cancer (OR = 10.35, 95% CI: 1.10 to 97.25, P = 0.041), while increased glycated hemoglobin levels increase pancreatic cancer risk (OR=2.33, 95% CI: 1.37 to 3.97, P=0.002) but decrease gastric cancer risk (OR=0.801, 95% CI: 0.65 to 0.99, P=0.044). Conclusion: T2DM is associated with a reduced risk of esophageal, gastric and colorectal cancer and hepatocellular carcinoma in East Asian populations. The causal relationships between T2DM with esophageal and gastric cancer are partially mediated by decreased fasting insulin and increased glycated hemoglobin levels, respectively. T2DM indirectly increases the risk of pancreatic cancer by increasing glycated hemoglobin levels.

The causality between leisure sedentary behaviors, physical activity and obstructive sleep apnea: a bidirectional Mendelian randomization study.

Background: Previous observational studies have shown a correlation between leisure sedentary behaviors (LSB) and physical activity (PA) with the incidence of obstructive sleep apnea (OSA). However, the causal associations remain unknown. Therefore, our study used bidirectional two-sample Mendelian randomization (MR) to identify potential causal relationships between LSB/PA and OSA. Methods: We sourced genetic variation data for LSB and PA from the UK Biobank, while data on OSA were collected from the FinnGen study. The primary analysis method employed was the inverse variance weighted (IVW) approach, complemented by the weighted median and MR-Egger methods. For sensitivity analyses, we conducted Cochran's Q test, the MR-Egger intercept test, the MR-PRESSO global test, and the leave-one-out analysis. Results: IVW analyses showed that genetically predicted leisure television watching (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.09-1.75, p = 0.007) and computer use (OR = 1.48, 95% CI = 1.15-1.92, p = 0.002) significantly increased the risk of OSA. Conversely, self-reported vigorous physical activity (VPA) (OR = 0.33, 95% CI = 0.11-0.98, p = 0.046) may reduce the risk of OSA. No causal effects on OSA risk were observed for driving or self-reported moderate-to-vigorous physical activity. Furthermore, the reverse MR analysis indicated no significant causal relationship between OSA and any LSB/PA phenotype. Sensitivity tests showed no significant heterogeneity or horizontal pleiotropy. Conclusion: This study suggests that leisurely television watching and computer use are risk factors for OSA, while VPA may be a protective factor. Additionally, OSA does not affect PA or LSB levels. We recommend reducing sedentary activities, particularly television watching and computer use, and prioritizing VPA to reduce the risk of OSA. Further research in diverse populations and settings is needed to validate these findings.

Micronutrient-Associated Single Nucleotide Polymorphism and Mental Health: A Mendelian Randomization Study.

PURPOSE: Previous studies have demonstrated the link between micronutrients and mental health. However, it remains uncertain whether this connection is causal. We aim to investigate the potential causal effects of micronutrients on mental health based on linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analysis. METHODS: Utilizing publicly available genome-wide association study (GWAS) summary datasets, we performed LDSC and MR analysis to identify candidate micronutrients with potential causal effects on mental health. Single nucleotide polymorphisms (SNPs) significantly linked with candidate micronutrients with a genome-wide significance level (p < 5 × 10-8) were selected as instrumental variables (IVs). To estimate the causal effect of candidate micronutrients on mental health, we employed inverse variance weighted (IVW) regression. Additionally, two sensitivity analyses, MR-Egger and weighted median, were performed to validate our results. RESULTS: We found evidence supporting significant causal associations between micronutrients and mental health. LDSC detected several candidate micronutrients, including serum iron (genetic correlation = -0.134, p = 0.032) and vitamin C (genetic correlation = -0.335, p < 0.001) for attention-deficit/hyperactivity disorder (ADHD), iron-binding capacity (genetic correlation = 0.210, p = 0.037) for Alzheimer's disease (AD), and vitamin B12 (genetic correlation = -0.178, p = 0.044) for major depressive disorder (MDD). Further MR analysis suggested a potential causal relationship between vitamin B12 and MDD (b = -0.139, p = 0.009). There was no significant heterogeneity or pleiotropy, indicating the validity of the findings. CONCLUSION: In this study, we identified underlying causal relationships between micronutrients and mental health. Notably, more research is necessary to clarify the underlying biological mechanisms by which micronutrients affect mental health.

Dried fruit intake and lower risk of type 2 diabetes: a two-sample mendelian randomization study.

BACKGROUND: Previous studies have shown controversy about whether dried fruit intake is associated with type 2 diabetes. This study aimed to examine the potential causal effect of dried fruit intake on type 2 diabetes by conducting a two-sample Mendelian randomization study. METHODS: We used genome-wide association study (GWAS) summary statistics for MR analysis to explore the causal association of dried fruit intake with T2D. The inverse-variance weighted (IVW) method was used as the main analytical method for MR analysis. In addition, the MR-Egger method and the weighted median method were applied to supplement the IVW method. Furthermore, Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis were used to perform sensitivity analysis. The funnel plot was used to assess publication bias. RESULTS: The results from the IVW analysis indicated that dried fruit intake could reduce the risk of T2D [odds ratio (OR) = 0.392, 95% confidence interval (CI): 0.241-0.636, p-value = 0.0001]. In addition, the result of additional method Weighted median is parallel to the effects estimated by IVW. Furthermore, the sensitivity analysis illustrates that our MR analysis was unaffected by heterogeneity and horizontal pleiotropy. Finally, the results of the leave-one-out method showed the robustness of our MR results. And the funnel plot shows a symmetrical distribution. CONCLUSION: Our study provides evidence for the benefits of dried fruit intake on T2D. Therefore, a reasonable consumption of dried fruit may provide primary prevention.

Causal association between immune cells and lung cancer risk: a two-sample bidirectional Mendelian randomization analysis.

Background: Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored. Methods: We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations. Results: Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (P<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (ORIVW =0.885; 95% CI: 0.798-0.983; P IVW =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (ORIVW =1.054; 95% CI: 1.010-1.100; P IVW =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (ORIVW =0.941; 95% CI: 0.898-0.987; P IVW =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) as well as on plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) in lung squamous cell carcinoma. Conclusion: This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.

Causal association between phenylalanine and Parkinson's disease: a two-sample bidirectional mendelian randomization study.

Background: Research findings indicate a putative indirect or latent association between phenylalanine (Phe) and Parkinson's disease (PD). In this study, we aimed to analyze the causal relationship between Phe and PD by two sample Mendelian randomization (MR) analysis. Methods: In this study, the PD-related dataset and Phe-related dataset were downloaded from Integrative Epidemiology U1nit (IEU) Open Genome-Wide Association Study (GWAS) database. Four algorithms (MR Egger, maximum likelihood, inverse variance weighting (IVW) and unweighted regression) were used to perform MR analysis. The sensitivity analysis (heterogeneity test, horizontal pleiotropy test and Leave-One-Out (LOO) analysis) was used to assess the reliability of MR analyses. Results: In the forward MR analysis, Phe was a safety factor for PD (p-value < 0.05 and odds ratios (OR) < 1). The results of reverse MR analysis showed that there was no causal relationship between PD and Phe (p-value > 0.05). In addition, sensitivity analysis showed that MR analysis was reliable. Conclusion: The results of this study revealed that Phe was a safety factor for PD, meaning that Phe reduced the risk of PD.

Robust evidence supports a causal link between higher birthweight and longer telomere length: a mendelian randomization study.

Background: Observational studies have suggested a potential relationship between birthweight and telomere length. However, the causal link between these two parameters remains undefined. In this study, we use Mendelian Randomization (MR). This method employs genetic variants as instrumental variables, to explore the existence of causal associations and elucidate the causal relationship between birth weight and telomere length. Methods: We used 35 single nucleotide polymorphisms (SNPs) as instrumental variables for birth weight. These SNPs were identified from a meta-analysis involving 153,781 individuals. Furthermore, we obtained summary statistics for telomere length from a study conducted on 472,174 United Kingdom Biobank participants. To evaluate the causal estimates, we applied the random effect inverse variance weighted method (IVW) and several other MR methods, such as MR-Egger, weighted median, and MR-PRESSO, to verify the reliability of our findings. Results: Our analysis supports a significant causal relationship between genetically predicted birth weight and telomer3e length. The inverse variance weighted analysis results for birth weight (Beta = 0.048; 95%CI = 0.023 to 0.073; p < 0.001) corroborate this association. Conclusion: Our study provides robust evidence supporting a causal link between higher birth weight and longer telomere length.

The causal relationship between sleep and risk of psychiatric disorders: A two-sample mendelian randomization study.

Introduction: Sleep is associated with psychiatric disorders. However, their causality remains unknown. Methods: The study explored the causal relationship between seven sleep parameters (sleep duration, insomnia, sleep apnea, chronotype, daytime dozing, napping during the day, and snoring) and three psychiatric disorders including major depressive disorder (MDD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD) using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS) summary data for sleep parameters were obtained from the United Kingdom biobank, FinnGen biobank, and EBI databases. MR-Egger, weighted median, inverse-variance weighted (IVW), simple mode, weighted mode, maximum likelihood, penalized weighted median, and IVW(fixed effects) were used to perform the MR analysis. The heterogeneity was detected by Cochran's Q statistic. The horizontal pleiotropy was detected by MR Egger. The sensitivity was investigated by the leave-one-out analysis. Results: Insomnia (OR = 2.02, 95%CI = 1.34-3.03, p = 0.001, False-discovery rate (FDR) corrected p-value = 0.011) and napping during the day (OR = 1.81, 95%CI = 1.34-2.44, FDR corrected p-value<0.001) were associated with an increased risk of MDD. Longer sleep duration (OR = 2.20, 95%CI = 1.24-3.90, FDR corrected p-value = 0.049) had an association with the increased risk of schizophrenia, while daytime dozing (OR = 4.44, 95%CI = 1.20-16.41, corrected p-value = 0.088)and napping during the day (OR = 2.11, 95%CI = 1.11-4.02, FDR corrected p-value = 0.088) had a suggestive association with an increased risk of schizophrenia. Longer sleep duration had a suggestive association with a decreased risk of ADHD (OR = 0.66, 95%CI = 0.42-0.93, FDR corrected p-value = 0.088). Conclusion: This study provides further evidence for a complex relationship between sleep and psychiatric disorders. Our findings highlight the potential benefits of addressing sleep problems in the prevention of psychiatric disorders.

Genetic association between asthma and alopecia areata: A two-sample Mendelian randomization study.

BACKGROUND: Many patients with asthma experience alopecia areata (AA) in their lives. However, it is unclear whether asthma causes or results from AA. Our objective was to investigate the genetic causal relationship between asthma and AA. METHODS: Two-sample Mendelian randomization (MR) was used to assess the causal relationship between asthma and AA based on the largest publicly available genome-wide association study summary statistics. Androgenetic alopecia (AGA) and cicatricial alopecia (CA) were chosen as the control groups for AA. The main estimates were obtained using inverse variance weighting meta-analysis (IVW), Mendelian randomization-Egger (MR-Egger), maximum likelihood estimation, and the weighted median. Sensitivity analyses were conducted using Cochran's Q test, MR-Egger, and leave-one-out methods. Lastly, we conducted a reverse MR analysis to evaluate the possibility of reverse causation. RESULTS: Genetically, asthma is associated with an increased risk of AA, while the association between genetically predicted AGA or CA and asthma was negative. The risk of AA increased by 1.86 times in patients with asthma under the IVW method (OR = 1.86, 95% CI = 1.31-2.629, p < 0.001). The reverse MR analysis did not find evidence supporting reverse causality from three phenotypes of alopecia to asthma. Sensitivity analyses yielded consistent causal estimates. CONCLUSION: This study suggests that asthma is causally associated with AA. The findings deepen our understanding of the role of asthma in the pathology of AA, which emphasizes the potential for opening a new vista for the prevention and diagnosis of AA.

The causal relationship between immune cells and Sjögren's syndrome: a univariate, multivariate, bidirectional Mendelian randomized study.

Introduction: Immune cells are involved in the onset and progression of Sjögren's syndrome (SS). This study explored the causal relationship between immune signature cells and SS, which has not been fully elucidated. Methods: We conducted univariate, multivariate, and bidirectional Mendelian randomization to investigate the causal relationship between 731 immunological feature characteristic cells and SS pairs and explore the interaction of immune cells in SS. Results: After false discovery rate correction, six immune cells were significantly associated with SS risk. Among them, four contributed to SS (CD24 on memory B cell, CD27 on IgD + CD24 + B cell, CD28 on CD39+ secreting CD4 Treg cell, and CD80 on CD62L + mDC); two appeared to reduce SS risk (CD3 on CD39 + CD8 + T cell and CD38 on IgD + CD38 + B cell). Pleiotropy and heterogeneity were not observed. Three immune cells exerted independent effects for SS (CD27 on IgD + CD24 + B cell, CD80 on CD62L + mDC, and CD38 on IgD + CD38 + B cell); two were risk factors (CD27 on IgD + CD24 + B cell and CD80 on CD62L + mDC); and one was a protective factor (CD38 on IgD + CD38 + B cell). Twenty-three immune cells showed a reverse causal relationship with SS. Conclusion: These findings demonstrate the influence of immune cells on SS risk and the effects of SS on immune cells, providing new clues for further research on the mechanisms underlying SS.

The role of digestive system diseases in cerebrovascular disease: a comprehensive Mendelian randomization study.

Background: Cerebrovascular disease, among the most prevalent neurological disorders, poses a substantial threat to human health with its elevated mortality and disability rates, placing considerable strain on healthcare systems. Although several studies in recent years have suggested a potential association between digestive system diseases and cerebrovascular diseases, the findings remain inconsistent. Methods: Genome-wide association study (GWAS) summary data for 12 digestive diseases and cerebrovascular diseases were used to conduct Mendelian randomization (MR) analysis. In this investigation, we endeavored to elucidate the causal relationship between digestive system diseases and cerebrovascular diseases. Employing a comprehensive approach, including two-sample MR (TSMR), multivariate MR (MVMR), and two-step MR analysis, we leveraged summary statistics data obtained from published GWAS. The primary analysis method employed was inverse variance weighted (IVW), with MR-Egger and weighted median (WM) as secondary methods. Sensitivity analysis included heterogeneity testing, horizontal multivariate testing, MR-PRESSO, and a "leave-one-out" method. Additionally, the F-statistic was utilized to assess the strength of instrumental variables, ensuring robust results. Results: In the TSMR analysis, this study found a significant causal relationship between genetically predicted gastroesophageal reflux disease (GERD) and any stroke (AS), any ischemic stroke (AIS), large-artery atherosclerotic stroke (LAS), intracranial aneurysm (IA), and subarachnoid hemorrhage (SAH). In MVMR analysis, this study found that even after adjusting for systolic blood pressure (SBP), body mass index (BMI) and type 2 diabetes (T2D), the causal relationship remains exist. In the two-step MR mediation analysis, it was found that BMI, SBP and T2D play mediating role in the causal relationship between GERD and cerebrovascular diseases. Conclusion: This study indicates a clear positive causal relationship between GERD and cerebrovascular diseases, and this causal association remains significant even after adjusting for BMI, SBP and T2D. The mediation MR analysis suggests that BMI, SBP and T2D may mediate the causal relationship between GERD and the risk of cerebrovascular diseases.

Causal association between type 2 diabetes mellitus and acute suppurative otitis media: insights from a univariate and multivariate Mendelian randomization study.

Background: Type 2 diabetes mellitus (T2DM) and hearing loss (HL) constitute significant public health challenges worldwide. Recently, the association between T2DM and HL has aroused attention. However, possible residual confounding factors and other biases inherent to observational study designs make this association undetermined. In this study, we performed univariate and multivariable Mendelian Randomization (MR) analysis to elucidate the causal association between T2DM and common hearing disorders that lead to HL. Methods: Our study employed univariate and multivariable MR analyses, with the Inverse Variance Weighted method as the primary approach to assessing the potential causal association between T2DM and hearing disorders. We selected 164 and 9 genetic variants representing T2DM from the NHGRI-EBI and DIAGRAM consortium, respectively. Summary-level data for 10 hearing disorders were obtained from over 500,000 participants in the FinnGen consortium and MRC-IEU. Sensitivity analysis revealed no significant heterogeneity of instrumental variables or pleiotropy was detected. Results: In univariate MR analysis, genetically predicted T2DM from both sources was associated with an increased risk of acute suppurative otitis media (ASOM) (In NHGRI-EBI: OR = 1.07, 95% CI: 1.02-1.13, P = 0.012; In DIAGRAM: OR = 1.14, 95% CI: 1.02-1.26, P = 0.016). Multivariable MR analysis, adjusting for genetically predicted sleep duration, alcohol consumption, body mass index, and smoking, either individually or collectively, maintained these associations. Sensitivity analyses confirmed the robustness of the results. Conclusion: T2DM was associated with an increased risk of ASOM. Strict glycemic control is essential for the minimization of the effects of T2DM on ASOM.

Assessment of the relationship between gut microbiota and bone mineral density: a two-sample Mendelian randomization study.

Background: Emerging evidence from observational studies and clinical trials suggests a connection between the gut microbiota and variations in bone mineral density (BMD). Nonetheless, the specific association between gut microbiota and BMD alterations at different skeletal sites has not been comprehensively explored. To address this, we employed Genome-Wide Association Study (GWAS) summary statistics from a publicly accessible database, conducting a two-sample Mendelian Randomization analysis to elucidate the potential causal relationship between gut microbiota composition and BMD. Methods: This study utilized two distinct thresholds for screening instrumental variables (IVs), followed by an extensive series of quality control procedures to identify IVs that were significantly related to exposure. Gut microbiota were classified into two sets based on hierarchical levels: phylum, class, order, family, and genus. Bone mineral density (BMD) data were systematically collected from four skeletal sites: femoral neck, lumbar spine, forearm, and heel. For Mendelian Randomization (MR) analysis, robust methods including Inverse-Variance Weighting (IVW) and the Wald Ratio Test were employed. Additional analytical tests such as the Outlier Test, Heterogeneity Test, 'Leave-One-Out' Test, and Pleiotropy Test were conducted to assess the impact of horizontal pleiotropy, heterogeneities, and the genetic variation stability of gut microbiota on BMD causal associations. The MR Steiger Directionality Test was applied to exclude studies with potential directional biases. Results: In this two-sample Mendelian randomization analysis, we utilized five sets of exposure GWAS (Genome-Wide Association Studies) summary statistics and four sets of outcome GWAS summary statistics. The initial analysis, applying a threshold of p < 5 × 10-6, identified 48 significant causal relationships between genetic liability in the gut microbiome and bone mineral density (BMD). A subsequent analysis with a more stringent threshold of p < 5 × 10-8 uncovered 14 additional causal relationships. Upon applying the Bonferroni correction, 9 results from the first analysis and 10 from the second remained statistically significant. Conclusion: Our MR analysis revealed a causal relationship between gut microbiota and bone mineral density at all sites, which could lead to discoveries in future mechanistic and clinical studies of microbiota-associated osteoporosis.

Investigation of the Causal Relationship Between Autoimmune Diseases and Premature Ovarian Insufficiency.

BACKGROUND: POI is a multifactorial disease due to lack of estrogen resulting in symptoms such as insomnia, osteoporosis, and voiding disorders. For most women, fertility is affected. Autoimmune diseases are chronic diseases caused by disorders of immune regulation that often harm the ovaries. Recent epidemiological studies have reported a correlation between autoimmune diseases (AIDs) and premature ovarian insufficiency (POI). This study aims to explore the causal relationship between AIDs and POI using bidirectional two-sample Mendelian randomization (MR). The data regarded AIDs from the Genome-wide association studies (GWAS) Catalog and the IEU Open GWAS project. POI was obtained from the FinnGen Study. All data were extracted from European populations. We used bidirectional MR with inverse variance weighting (IVW) as the primary study method, supplemented by weighted median and MR Egger validation analyses. Our original data has been uploaded to Figshare, number and distribution of the DOI (DOI: 10.6084 / m9 Figshare. 25,525,585). Figshare is an open-access data storage and sharing platform designed to make it easy for researchers to store, manage, and share their research data, code, and other academic achievements. Our study showed that the liability to Systemic lupus erythematosus (SLE) and Myasthenia gravis (MG) affect POI risk. The reverse MR analysis supported the effect of POI on Crohn's disease (CD). The result of the IVW method was supported by the sensitivity MR analysis. The IVW results showed that the odds ratio (OR) value of SLE was 1.13 and MG was 0.83. In the reverse MR, the OR value of CD was 1.22. We used MR methods to look into the causal association between 13 different kinds of AIDs and POI. Our study took a novel approach to traditional observational studies by adhering to the MR principle, which states that gamete formation depends on random assortment independent of external variables and that genetic variations precede outcomes, reducing the risk of reverse causality. The study found a correlation between SLE, MG, CD, and POI. Patients with SLE should have their ovarian function checked regularly, while those with POI should be aware of the possibility of CD and pay attention to their CD screening. MG, as a protective factor, can reduce the risk of POI.