Bidirectional Mendelian Randomization Reveals Causal Effects of Immune Cell Traits on Endometriosis Risk.

PURPOSE: Previous studies have identified associations between immune cell traits and endometriosis, but the causality of these relationships remains uncertain. In this study, we utilized Mendelian randomization (MR) to investigate the causal relationship between immune cell traits and endometriosis for the first time. METHODS: Seven hundred and thirty-one immune cell signatures associated with single-nucleotide polymorphisms (SNPs) were extracted from a published genome-wide association study (GWAS) involving 472 174 individuals, while endometriosis data, including four stages and seven subtypes, were obtained from the FinnGen consortium. Four methods were used for MR. The causal effect of immune cell traits on endometriosis was explored after Bonferroni correction. RESULTS: Significant causal relationship included 92 immune cell traits distributed among B cell (28 cells), cDC (2 cells), maturation stages of T cell (10 cells), monocyte (12 cells), Myeloid cell (5 cells), TBNK (13 cells), and Treg panels (22 cells). One of the most significant findings is that for every 1-standard deviation (SD) increase in CD8 on Central Memory CD8+ T cell, the risks of developing endometriosis of the fallopian tube increased by 72%. In the reverse MR analysis, a one-unit increase in the log odds of endometriosis of the ovary risk corresponded to a decrease in the absolute count of CD4+ CD8dim T cell by 0.10. CONCLUSION: This study represents the first comprehensive evaluation of the causal effects of immune cell traits on the risk/protection of different stages/subtypes of endometriosis. The findings highlight the complex and significant role of immune-derived factors in the pathogenesis of the disease.

Causal relationship between non-alcoholic fatty liver disease and sarcopenia: a bidirectional Mendelian randomization study.

Introduction: A correlation between non-alcoholic fatty liver disease and sarcopenia is demonstrated, but the causality remains unclear. Our study aims to clarify the point of genetics between non-alcoholic fatty liver disease (NAFLD) and sarcopenia at the level of gene prediction through two-sample Mendelian randomization (MR) analysis. Methods: The study employed the two-sample MR approach to investigate the bi-directional causality between NAFLD and sarcopenia. Published summary statistics were used to obtain instrumental variables (IVs) at the genome-wide significance level. Results: IVW analysis showed that the risk of NAFLD was reduced when walking pace was increased (OR = 0.435, 95%CI 0.240-0.789, p = 0.006); Increasing appendicular lean mass (ALM) decreased the risk of NAFLD (OR = 0.906, 95%CI 0.838-0.980, p = 0.014); Those older than 60 were more likely to suffer from NAFLD if they had low grip strength (OR = 1.411, 95%CI 1.087-1.830, p = 0.0012). In the reverse MR study, weight median analysis showed that NAFLD caused a decrease in ALM (OR = 0.953, 95%CI 0.957-0.994, p = 0.001); whereas NAFLD showed no correlation with usual walking pace or grip strength (all with p > 0.05). MR-Egger regression analysis showed that there was no horizontal pleiotropy in the SNPs (all with p > 0.05). Conclusion: The characteristics related to sarcopenia (usual walking pace, appendicular lean mass and low hand grip strength) may play a causal role in the development of nonalcoholic fatty liver disease, although the underlying mechanisms need to be further investigated. The presence of specific single nucleotide polymorphisms (SNPs) such as rs3747207, rs429358, and rs73001065 has been identified in the PNPLA3, APOE, and MAU2 proteins. These genetic markers represent potential targets for future interventions aimed at addressing, managing, or mitigating the risk of NAFLD.

Causal relationship between green tea intake and gastrointestinal disorders: a two-sample Mendelian randomization study.

Background: The precise association between green tea intake and gastrointestinal disorders remains controversial. This study aimed to investigate the potential causal association between green tea intake and gastrointestinal disorders through a two-sample Mendelian randomization (MR) study. Methods: Utilizing publicly accessible data from genome-wide association studies (GWAS), we identified SNPs strongly linked with the study variables from multiple large databases to serve as instrumental variables (IVs). MR analyses were executed utilizing the inverse variance weighting (IVW) method, with the resultant effect estimates serving as the primary outcome measure. In addition, a multivariate MR design was performed to adjust for smoking and alcohol consumption. To ensure the robustness of our findings, a series of sensitivity analyses were conducted to assess reliability. Results: Univariable MR analysis revealed suggestive associations between green tea intake and gastroesophageal reflux (OR = 0.9950, 95% CI 0.9900-1.0000, p IVW = 0.047), diverticulosis (OR = 0.9998, 95% CI 0.9996-1.0000, p IVW = 0.030), Crohn's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p IVW = 0.019), and cholangitis was observed (OR = 1.0440, 95% CI 1.0100-1.0790, p IVW = 0.011). Multivariate MR analysis indicated after controlling for potential confounders, greater green tea consumption was suggestively associated with the decreased risk of oesophagitis (OR = 0.9667, 95% CI: 0.9405-0.9936, p IVW = 0.016) and gastric cancer (OR = 0.9810, 95% CI: 0.9628-0.9996, p IVW = 0.046). Nevertheless, multivariate MR analysis also showed that greater green tea consumption was suggestively associated with the increased risk of Crohn's disease (OR = 1.0001, 95% CI: 1.0000-1.0002, p IVW = 0.007). Sensitivity analyses confirmed that these results were reliable. Conclusion: Our study provides suggestive evidence that genetically predicted green tea intake is causally associated with the risk of oesophagitis, gastric cancer and Crohn's disease, but a larger GWAS database is needed for validation.

Investigation of the causal relationship between cholelithiasis and Parkinson's disease: A bidirectional Mendelian randomization study.

Background: Parkinson's disease (PD) and cholelithiasis are a huge public health burden. Although observational studies have suggested a potential link between PD and cholelithiasis, the causal relationship between the two remains uncertain. To address this gap, we performed a two-sample bidirectional Mendelian randomization analysis using genetic tools. Method: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. We used strict control steps in instrumental variable selection to screen for single nucleotide polymorphisms (SNPs) from summary-level genome-wide association studies. In addition, all F-statistics were >10, indicating no weak instrumental bias. The inverse variance weighting (IVW) method was the primary method used to assess causal associations. Four other MR methods (MR-Egger, Weighted Median, Simple mode, and Weighted mode) were also used to complement IVW. Various sensitivity tests were also performed to assess reliability: (1) Cochrane's Q test for assessing heterogeneity, (2) MR-Egger intercept test and MR-PRESSO global test for assessing horizontal multiplicity, and (3) leave-one-out sensitivity test for determining stability. Results: We selected a total of 30 SNPs as instrumental variables. It was demonstrated that cholelithiasis had a causal effect on the risk of PD (OR = 1.146, 95% CI: 1.062-1.236, p < 0.001) in IVW method. Conclusion: The results of our analysis revealed an increased risk effect of cholelithiasis against PD, which may give light on new approaches to PD prevention and therapy.

Traumatic brain injury increasing risk of meningioma? From the genetic evidence.

BACKGROUND: Numerous studies have demonstrated a strong association between traumatic brain injury (TBI) and an increased risk of meningioma. However, this correlation remains controversial. This study utilized mendelian randomization to explore this relationship from perspective of genetic evidence. METHODS: We employed six traumatic brain injury genome-wide association study (GWAS) datasets from the IEU GWAS database. Summary statistics for meningioma were sourced from the FinnGen R10 database. We assessed heterogeneity and horizontal pleiotropy within the analyzed data. The primary method was inverse variance weighting (IVW) to investigate the causal relationship between TBI and meningioma, excluding cases with horizontal pleiotropy. Four supplementary analysis methods were also used, with abnormal results excluded based on leave-one-out sensitivity analysis. RESULTS: All six Mendelian randomization analyses indicated no causal relationship between TBI and meningiomas (Focal brain injury IVW p-value = 0.98; Diffuse brain injury IVW p-value = 0.41; TBI without concussion IVW p-value = 0.45; Intracranial trauma IVW p-value = 0.34; Traumatic subdural hemorrhage IVW p-value = 0.80; Traumatic subarachnoid hemorrhage IVW p-value = 0.92). CONCLUSIONS: The mendelian randomization study revealed that traumatic brain injury does not increase the risk of meningioma based on genetic evidence.

The Causal Relationship Between Physical Activity and Skin Cancer Risk: An Univariable Mendelian Randomization Study.

Background: The existing observational research on the relationship between physical activity (PA) and skin cancer (SC) is contentious, which points to the intricate nature of their association and underscores the imperative for more nuanced research to untangle the causal dynamics at play. The aim of this article is to delve deeper into this complex relationship, seeking to clarify whether PA serves as a protective factor against SC, or contributes to its risk. Methods: We utilized data from the genome-wide association study (GWAS) of PA from GWAS Catalog (include self-reported moderate to vigorous PA (MVPA), self-reported vigorous PA (VPA), and accelerometer-based average-accelerated PA). The data of SC is from FinnGen. All of the participants are of European ancestry. We used two-sample Mendelian Randomization (TSMR) to analyze the causal relationship between PA and SC.The research was conducted using inverse variance weighted (IVW) method as the primary approach, and MR Egger regression as supplementary analytical method. To ensure the robustness of the results, Cochran's Q-test and MR pleiotropy residual sum and outlier (MR-PRESSO) global tests were used to measure sensitivity. Results: Our analysis indicated that average-accelerated PA was associated with an increased risk of SC (ORIVW = 0.94, 95% CI 0.93-0.96, P < 0.001). While neither MVPA (ORIVW = 0.99, 95% CI 0.67-1.47, P = 0.962) nor VPA (ORIVW = 0.80, 95% CI 0.29-2.18, P = 0.656) shows causal relationship on risk of SC. Conclusion: Our research suggests that PA is associated with a decrease in SC, provides a new perspective for future SC prevention. Our research findings bolster the hypothesis that increased levels of PA, characterized by average acceleration, are associated with a reduced risk of developing skin cancer. This has filled the gap of research on the causal relationship between PA and SC, and could pave the way for novel preventive strategies against skin cancer.

Causal relationships between gut microbiome and aplastic anemia: a Mendelian randomization analysis.

BACKGROUND: Previous observational studies have hinted at a potential correlation between aplastic anemia (AA) and the gut microbiome. However, the precise nature of this bidirectional causal relationship remains uncertain. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the potential causal link between the gut microbiome and AA. Statistical analysis of the gut microbiome was based on data from an extensive meta-analysis (genome-wide association study) conducted by the MiBioGen Alliance, involving 18,340 samples. Summary statistical data for AA were obtained from the Integrative Epidemiology Unit database. Single -nucleotide polymorphisms (SNPs) were estimated and summarized using inverse variance weighted (IVW), MR Egger, and weighted median methods in the bidirectional MR analysis. Cochran's Q test, MR Egger intercept test, and sensitivity analysis were employed to assess SNP heterogeneity, horizontal pleiotropy, and stability. RESULTS: The IVW analysis revealed a significant correlation between AA and 10 bacterial taxa. However, there is currently insufficient evidence to support a causal relationship between AA and the composition of gut microbiome. CONCLUSION: This study suggests a causal connection between the prevalence of specific gut microbiome and AA. Further investigation into the interaction between particular bacterial communities and AA could enhance efforts in prevention, monitoring, and treatment of the condition.

Genetically predicted the causal relationship between gut microbiota and the risk of polymyositis/dermatomyositis: a Mendelian randomization analysis.

Introduction: Observational studies suggest associations between gut microbiota and polymyositis (PM) and dermatomyositis (DM), but causal relationships are unclear. We investigate the causal effects of gut microbiota on PM and DM, providing insights hoping to provide insights for future treatment and prevention. Methods: Summary statistics of gut microbiota were obtained from a multi-ethnic Genome Wide Association Studies (GWAS) meta-analysis, including 119 taxa from 18,340 Europeans. PM/DM statistics were extracted from GWAS analyses. Mendelian randomization (MR) with IVW, MR-Egger, and weighted median methods was performed. Sensitivity analyses addressed heterogeneity and pleiotropy. Of the 119 bacterial genera studied, six showed causal links. Results: Alloprevotella (OR: 3.075, 95% CI: 1.127-8.386, p = 0.028), Ruminococcaceae UCG003 (OR: 4.219, 95% CI: 1.227-14.511, p = 0.022), Dialister (OR: 0.273, 95% CI: 0.077-0.974, p = 0.045) were associated with PM. Anaerotruncus (OR: 0.314, 95% CI: 0.112-0.882, p = 0.028), Ruminococcaceae UCG002 (OR: 2.439, 95% CI: 1.173-5.071, p = 0.017), Sutterella (OR: 3.392, 95% CI: 1.302-8.839, p = 0.012) were related to DM. Sensitivity analyses validated these associations. Discussion: We establish causal relationships between Ruminococcaceae, Sutterella, Anaerotruncus with DM, Alloprevotella, Ruminococcaceae UCG003, and Dialister with PM. Common microbiota, like Ruminococcaceae, have significant clinical implications. These findings open up greater possibilities for the gut microbiota to contribute to the development of PM/DM and for future monitoring of the gut microbiota in patients with PM/DM.

Exploring the causal relationship between the immune cell-inflammatory factor axis and lung cancer: a Mendelian randomization study.

Background: Lung cancer is a major health burden globally and smoking is a well-known risk factor. It has been observed that chronic inflammation contributes to lung cancer progression, with immune cells and inflammatory cytokines implicated in tumor development. Clarifying the causal links between these immune components and lung cancer could enhance prevention and therapy. Methods: We performed Mendelian randomization (MR) to explore causal connections between immune cells, inflammatory markers, and lung cancer risk, using genetic variants as instruments. Data from GWAS on these variables underpinned our MR analyses. Results: Our findings indicated an inverse association between some immune cells and lung cancer risk, implying that more immune cells might be protective. NK T cells (CD16-CD56) and myeloid cells (HLA DR+ on CD33dim HLA DR+ CD11b+) had an inverse correlation with lung cancer risk. Furthermore, a direct relationship was observed between inflammatory cytokines and these immune cells. In contrast, IL-18 was inversely associated with lung cancer, while IL-13 showed a direct correlation. Conclusion: The study underscores the role of immune and inflammatory factors in lung cancer. These insights could lead to new therapeutic strategies for combating lung cancer.

The causal effect of hot beverage temperature preference on esophageal cancer risk: a Mendelian randomization study.

Background: Previous research has found a link between the temperature of food and beverages and the risk of esophageal cancer (EC). A causal relationship between the two has not been well established. Herein, we used Mendelian randomization (MR) analysis to assess the causal effect of temperature preference for hot beverages on EC risk. Methods: Genome-wide association studies (GWAS) data for hot beverage temperature preference were obtained from the UK biobank. There were 457,873 European and 2,617 East Asian participants included. GWAS data for EC were obtained from the Integrative Epidemiology Unit (IEU) project database. Two datasets from the European population and two datasets from the East Asian population were included. Totally, 4,426 EC cases and 1,202,270 control subjects were included. The "TwoSampleMR" R package was used to conduct a two-sample MR analysis. A random-effect inverse variance weighted (IVW) was used as the main analytical method to estimate the causal effect, and various sensitivity analyses, including MR Egger, weighted median, simple mode, and weighted mode, were used to examine the potential violation of the second and third MR assumptions. Meta-analyses were performed to further confirm the results. Results: Sixty-eight single nucleotide polymorphisms (SNPs) from the European population and 11 SNPs from the East Asian population were used for MR analysis. No significant causal effect was found between hot beverage temperature preference and EC risk in the European population {for the ieu-b-4960 dataset, inverse variance weighted odds ratio (ORIVW) =1.00 [95% confidence interval (CI): 0.99-1.00], P=0.54; for the ebi-a-GCST90018841 dataset, ORIVW =0.35 (95% CI: 0.10-1.29), P=0.12} or in the East Asian population [for the bbj-a-117 dataset, ORIVW =1.09 (95% CI: 0.80-1.48), P=0.59; for the ebi-a-GCST90018621 dataset, ORIVW =0.11 (95% CI: 0.82-1.50), P=0.49]. Meta-analyses of the European population datasets and the Asian population datasets showed consistent results. Conclusions: The current MR analysis provides new genetic evidence for a null causal relationship between hot beverage temperature preference and EC, both in the European population and the East Asian population. Evidence to prevent EC by reducing the intake of hot beverages is insufficient.

Causal relationship between gut microbiota and male erectile dysfunction: a Mendelian randomization analysis.

Background: Several observational studies have reported an association between gut microbiota and male erectile dysfunction (ED). However, it remains unclear whether there is a causal relationship between gut microbiota and male ED. Thus, we aimed to investigate the potential causal relationship between gut microbiota and male ED through Mendelian randomization (MR) analysis. Objective: To assess the causal relationship between gut microbiota and male ED, we performed a two-sample MR analysis. Methods: We obtained gut microbiota genome-wide association studies (GWAS) data from the MiBioGen consortium and publicly available GWAS data on male ED from the OPEN GWAS database. Subsequently, we performed a two-sample MR analysis to evaluate the causal relationship between gut microbiota and male ED. Finally, we performed sensitivity analysis, including Cochran's Q test, MR-Egger intercept analysis, MR-PRESSO, and leave-one-out analysis, to assess the level of heterogeneity and horizontal pleiotropy in the results. Results: Our MR analysis revealed a negative causal relationship between the genus Ruminococcaceae UCG013 and male ED (OR = 0.761, 95% CI 0.626-0.926), while the family Lachnospiraceae, genus Lachnospiraceae NC2004 group, genus Oscillibacter, and genus Tyzzerella3 may be associated with an increased risk of male ED, with the highest risk observed for family Lachnospiraceae (OR = 1.264, 95% CI 1.063-1.504). Furthermore, sensitivity analysis confirmed the reliability of our positive findings. Conclusion: Our MR analysis revealed a causal relationship between gut microbiota and male ED. This may contribute to a better understanding of the potential applications of gut microbiota in the occurrence and treatment of male ED.

Metabolic Characteristics of Gut Microbiota and Insomnia: Evidence from a Mendelian Randomization Analysis.

Insomnia is a common sleep disorder that significantly impacts individuals' sleep quality and daily life. Recent studies have suggested that gut microbiota may influence sleep through various metabolic pathways. This study aims to explore the causal relationships between the abundance of gut microbiota metabolic pathways and insomnia using Mendelian randomization (MR) analysis. This two-sample MR study used genetic data from the OpenGWAS database (205 gut bacterial pathway abundance) and the FinnGen database (insomnia-related data). We identified single nucleotide polymorphisms (SNPs) associated with gut bacterial pathway abundance as instrumental variables (IVs) and ensured their validity through stringent selection criteria and quality control measures. The primary analysis employed the inverse variance-weighted (IVW) method, supplemented by other MR methods, to estimate causal effects. The MR analysis revealed significant positive causal effects of specific carbohydrate, amino acid, and nucleotide metabolism pathways on insomnia. Key pathways, such as gluconeogenesis pathway (GLUCONEO.PWY) and TCA cycle VII acetate producers (PWY.7254), showed positive associations with insomnia (B > 0, p < 0.05). Conversely, pathways like hexitol fermentation to lactate, formate, ethanol and acetate pathway (P461.PWY) exhibited negative causal effects (B < 0, p < 0.05). Multivariable MR analysis confirmed the independent causal effects of these pathways (p < 0.05). Sensitivity analyses indicated no significant pleiotropy or heterogeneity, ensuring the robustness of the results. This study identifies specific gut microbiota metabolic pathways that play critical roles in the development of insomnia. These findings provide new insights into the biological mechanisms underlying insomnia and suggest potential targets for therapeutic interventions. Future research should further validate these causal relationships and explore how modulating gut microbiota or its metabolic products can effectively improve insomnia symptoms, leading to more personalized and precise treatment strategies.

Inferring gene regulatory networks with graph convolutional network based on causal feature reconstruction.

Inferring gene regulatory networks through deep learning and causal inference methods is a crucial task in the field of computational biology and bioinformatics. This study presents a novel approach that uses a Graph Convolutional Network (GCN) guided by causal information to infer Gene Regulatory Networks (GRN). The transfer entropy and reconstruction layer are utilized to achieve causal feature reconstruction, mitigating the information loss problem caused by multiple rounds of neighbor aggregation in GCN, resulting in a causal and integrated representation of node features. Separable features are extracted from gene expression data by the Gaussian-kernel Autoencoder to improve computational efficiency. Experimental results on the DREAM5 and the mDC dataset demonstrate that our method exhibits superior performance compared to existing algorithms, as indicated by the higher values of the AUPRC metrics. Furthermore, the incorporation of causal feature reconstruction enhances the inferred GRN, rendering them more reasonable, accurate, and reliable.

Causal relationship between circulating glutamine levels and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with a median survival of less than 5 years. In recent years, glutamine has been reported to be involved in the regulation of collagen deposition and cell proliferation in fibroblasts, thereby influencing the progression of IPF. However, the relationships between glutamine and the incidence, progression, and treatment response of IPF remain unclear. Our study aimed to investigate the relationship between circulating glutamine levels and IPF, as well as its potential as a therapeutic target. METHODS: We performed a comprehensive Mendelian Randomization (MR) analysis using the most recent genome-wide association study summary-level data. A total of 32 single nucleotide polymorphisms significantly correlated to glutamine levels were identified as instrumental variables. Eight MR analysis methods, including inverse variance weighted, MR-Egger, weighted median, weighted mode, constrained maximum likelihood, contamination mixture, robust adjusted profile score, and debiased inverse-variance weighted method, were used to assess the relationship between glutamine levels with IPF. RESULTS: The inverse variance weighted analysis revealed a significant inverse correlation between glutamine levels and IPF risk (Odds Ratio = 0.750; 95% Confidence Interval : 0.592-0.951; P = 0.017). Sensitivity analyses, including MR-Egger regression and MR-PRESSO global test, confirmed the robustness of our findings, with no evidence of horizontal pleiotropy or heterogeneity. CONCLUSION: Our study provides novel evidence for a causal relationship between lower circulating glutamine levels and increased risk of IPF. This finding may contribute to the early identification of high-risk individuals for IPF, disease monitoring, and development of targeted therapeutic strategies.

No genetic causal association between human papillomavirus and lung cancer risk: a bidirectional two-sample Mendelian randomization analysis.

INTRODUCTION: Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis. METHODS: In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 - 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 - 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 - 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 - 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 - 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 - 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 - 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 - 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 - 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 - 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 - 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 - 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection. CONCLUSIONS: Our findings do not support a genetic association between HPV infection and lung cancer.

Causal effects of gut microbiota on risk of overactive bladder symptoms: a two-sample Mendelian randomization study.

Background: Clinical observations indicate a correlation between the gut microbiota and overactive bladder (OAB) symptoms. Nevertheless, the causal relationship and mechanisms between gut microbiota and OAB symptoms remain elusive. Methods: Two-sample Mendelian randomization (MR) analyses were performed to assess the association between gut microbiota and OAB symptoms, including urinary incontinence (UI). Data were obtained from the MiBioGen International Consortium genome-wide association studies (GWAS) dataset and the IEU GWAS database. The inverse variance weighted method was used as the primary approach in the MR analysis, with the weighted median, MR-Egger, and weighted mode methods as supplementary approaches. Sensitivity analyses were employed to assess potential violations of the MR assumptions. Results: Our analysis identified seven gut bacterial taxa with a causal relationship to OAB and nine gut bacterial taxa associated with UI. Genera Eubacteriumfissicatenumgroup, LachnospiraceaeNK4A136group, and Romboutsia were identified as protective factors against OAB, while genera Barnesiella, FamilyXIIIAD3011group, Odoribacter, and RuminococcaceaeUCG005 were associated with an increased risk of OAB. A higher abundance of the genus Coprococcus3, order Burkholderiales, and phylum Verrucomicrobia predicted a lower risk of UI. Conversely, the class Mollicutes, genus Ruminococcus gauvreauii group, order Mollicutes RF9, and phylum Firmicutes and Tenericutes were positively correlated with UI risk. The sensitivity analysis excluded the influence of potential heterogeneity and horizontal pleiotropy. Conclusion: This study revealed a causal relationship between gut microbiota and OAB symptoms, providing new insights and a theoretical foundation to identify biomarkers and therapeutic targets for patients with OAB symptoms.

Blood cell counts and nonalcoholic fatty liver disease: Evidence from Mendelian randomization analysis.

BACKGROUND: Previous research has highlighted correlations between blood cell counts and chronic liver disease. Nonetheless, the causal relationships remain unknown. AIM: To evaluate the causal effect of blood cell traits on liver enzymes and nonalcoholic fatty liver disease (NAFLD) risk. METHODS: Independent genetic variants strongly associated with blood cell traits were extracted from a genome-wide association study (GWAS) conducted by the Blood Cell Consortium. Summary-level data for liver enzymes were obtained from the United Kingdom Biobank. NAFLD data were obtained from a GWAS meta-analysis (8434 cases and 770180 controls, discovery dataset) and the Fingen GWAS (2275 cases and 372727 controls, replication dataset). This analysis was conducted using the inverse-variance weighted method, followed by various sensitivity analyses. RESULTS: One SD increase in the genetically predicted haemoglobin concentration (HGB) was associated with a ß of 0.0078 (95%CI: 0.0059-0.0096), 0.0108 (95%CI: 0.0080-0.0136), 0.0361 (95%CI: 0.0156-0.0567), and 0.0083 (95%CI: 00046-0.0121) for alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase, and gamma-glutamyl transferase, respectively. Genetically predicted haematocrit was associated with ALP (ß = 0.0078, 95%CI: 0.0052-0.0104) and ALT (ß = 0.0057, 95%CI: 0.0039-0.0075). Genetically determined HGB and the reticulocyte fraction of red blood cells increased the risk of NAFLD [odds ratio (OR) = 1.199, 95%CI: 1.087-1.322] and (OR = 1.157, 95%CI: 1.071-1.250). The results of the sensitivity analyses remained significant. CONCLUSION: Novel causal blood cell traits related to liver enzymes and NAFLD development were revealed through Mendelian randomization analysis, which may facilitate the diagnosis and prevention of NAFLD.

Exploring the genetic causal relationship between physical activity and migraine in European population based on Mendelian randomization analysis.

Background: Previous studies have shown a connection between physical activity and migraines, but they don't prove a cause-and-effect relationship due to potential biases in observational methods. Methods: Utilizing accelerometer-measured physical activity data from a cohort of 377,234 participants in the UK Biobank and information from 599,356 European migraine patients (including 48,975 cases and 550,381 controls) obtained from 24 cohorts, we performed a bidirectional Mendelian randomization analysis to investigate the genetic bidirectional causal relationship between accelerometer-measured physical activity and migraines. Results: Research findings indicated a slight negative genetic correlation between "average acceleration" physical activity (rg = -0.091, p = 0.011), overall physical activity (rg = -0.081, p = 0.017), and migraine. Nevertheless, no shared genetic components were observed between migraine and "fraction of accelerations > 425 mg" of physical activity (rg = -0.124, p = 0.076). The study results also demonstrated a lack of genetic bidirectional causality between accelerometer-measured physical activity and migraine ("average acceleration", OR = 1.002, 95% CI 0.975-1.031, p = 0.855, "fraction of accelerations > 425 mg", OR = 1.127, 95% CI 0.802-1.583, p = 0.488, overall physical activity, OR = 0.961, 95% CI 0.713-1.296, p = 0.799), and vice versa. Additionally, this lack of causal association persists even after adjusting for obesity (OR = 1.005, p = 0.578), education (OR = 1.019, p = 0.143), and depression (OR = 1.005, p = 0.847), either separately or simultaneously. Conclusion: The Mendelian randomization results based on genetic data do not provide support for a causal association between physical activity and migraine.

Assessing the causal effect of inflammation-related genes on myocarditis: A Mendelian randomization study.

AIMS: Prior evidence has shown a significant link between inflammation and the development of myocarditis. This study aimed to investigate the causal relationship between inflammation-related genes (IRGs) and myocarditis. METHODS AND RESULTS: In this study, the causal relationship between 167 IRGs and myocarditis were investigated using datasets from the Gene Set Enrichment Analysis and Integrative Epidemiology Unit open genome-wide association study (IEU OpenGWAS) databases. The GWAS data (finn-b-I9 MYOCARD) contained single nucleotide polymorphisms (SNPs) data from 117 755 myocarditis samples (16 379 455 SNPs, 829 cases vs. 116 926 controls). Five algorithms [MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode regression] were employed for the MR analysis, with IVW as the primary method, and sensitivity analysis was conducted. Subcellular localization and protein-protein interaction (PPI) network analyses were performed for selected biomarkers. Results were verified in ebi-a-GCST90018882 (24 180 570 SNPs, 633 cases vs. 427 278 controls) and finn-b-I9 MYOCARD EXNONE (16 380 466 SNPs, 829 cases vs. 217 963 controls) to enhance reliability. RESULTS: IRF7 and ADORA2B were shown to be two exposure factors after screening. Univariable MR (UVMR) analysis revealed that IRF7 was a risk factor for myocarditis [IVW: odd ratio (OR) = 1.041, 95% confidence interval (CI) = 1.018-1.955, P = 0.039], while ADORA2B was a protective factors for myocarditis (IVW: OR = 0.799, 95% CI = 0.640-0.997, P = 0.047). Sensitivity analysis confirmed the robustness of these findings. Multivariable MR (MVMR) analysis further demonstrated a direct causal role of ADORA2B in preventing myocarditis. Subcellular localization analysis indicated predominant cytoplasmic expression and limited mitochondrial expression for both genes. The results of PPI analysis showed that 20 genes were predicted to be associated with IRF7 function, such as response to type I interferon, pattern recognition receptor signalling pathway, and toll-like receptor signalling pathway. The results in finn-b-I9 MYOCARD EXNONE were consistent with MR analysis. CONCLUSIONS: The findings indicated there was a causal connection between IRGs (IRF7 and ADORA2B) and myocarditis, which offered a crucial point of reference and guidance for future studies and myocarditis treatment.

Dissecting the causal relationship between moderate to vigorous physical activity levels and cognitive performance: a bidirectional two-sample Mendelian randomization study.

Introduction: Recent studies increasingly suggest that moderate-to-vigorous physical activity (MVPA) impacts cognitive risk. However, the bidirectional nature of this relationship warrants further exploration. To address this, we employed a Mendelian randomization (MR) approach, analyzing two distinct samples. Methods: These analyses utilized published genome-wide association study (GWAS) summary statistics for MVPA (n = 377,234) and cognitive performance (n = 257,841). Our primary method was the inverse variance weighted (IVW) model with random effects, aiming to deduce potential causal links. Additionally, we employed supplementary methods, including MR Egger regression, Weighted median, Weighted mode, and Simple mode. For sensitivity analysis, tools like the MR Egger test, Cochran's Q, MR PRESSO, and leave-one-out (LOO) were utilized. Results: Our findings indicate a decrease in cognitive risk with increased MVPA (Odds Ratio [OR] = 0.577, 95% Confidence Interval [CI]: 0.460-0.723, p = 1.930 × 10-6). Furthermore, enhanced cognitive levels corresponded to a reduced risk of inadequate MVPA (OR = 0.866, 95% CI: 0.839-0.895, p = 1.200 × 10-18). Discussion: In summary, our study demonstrates that MVPA lowers cognitive risk, while poor cognitive health may impede participation in MVPA. Overall, these findings provide valuable insights for developing personalized prevention and intervention strategies in health and sports sciences.