Significant Causal Association Research Articles

Causal effects of sedentary behaviours on the risk of migraine: A univariable and multivariable Mendelian randomization study.

Migraine is a common and burdensome neurological disorder. The causal relationship between sedentary behaviours (SBs) and migraine remains instinct. We aimed to evaluate the roles of SBs including watching TV, using computer and driving in the risk of migraine. We conducted a univariable and multivariable Mendelian randomization (MR) study based on summary datasets of large genome-wide association studies. The inverse variance weighted method was utilized as the primary analytical tool. Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier and leave-one-out were conducted as sensitivity analysis. Additionally, we performed a meta-analysis to combine the causal estimates. In the discovery analysis, we identified causal associations between time spent watching TV and an increased risk of migraine (p = 0.015) and migraine without aura (MO) (p = 0.002). Such causalities with increasing risk of migraine (p = 0.005), and MO (p = 0.006) were further verified using summary datasets from another study in the replication analysis. There was no significant causal association found between time spent using computer, driving and migraine or its two subtypes. The meta-analysis and multivariable MR analysis also strongly supported the causal relationships between time spent watching TV and an increased risk of migraine (p = 0.0003 and p = 0.034), as well as MO (p < 0.0001 and p = 0.0004), respectively. These findings were robust under all sensitivity analysis. Our study suggested that time spent watching TV may be causally associated with an increased risk of migraine, particularly MO. Large-scale and well-designed cohort studies may be warranted for further validation. This study represents the first attempt to investigate whether a causal relationship exists between SBs and migraine. Utilizing MR analysis helps mitigate reverse causation bias and confounding factors commonly encountered in observational cohorts, thereby enhancing the robustness of derived causal associations. Our MR analysis revealed that time spent watching TV may serve as a potential risk factor for migraine, particularly MO.

The impact of depression-mediated gut microbiota composition on Irritable Bowel Syndrome: A Mendelian study

ObjectiveThis study uses a two-sample Mendelian randomization (MR) analysis to delineate the causal influence of gut microbiota on the occurrence of irritable bowel syndrome (IBS), concurrently assessing the potential mediating function of depression within this framework. MethodsSeveral two-sample MR methods were used to assess the causal repercussions of gut microbiota on the onset of both IBS and depression. Following this, gut microbiota and depression, which demonstrated notable causal associations, were integrated as exposure variables in a multivariable Mendelian randomization (MVMR) framework to construct a model encompassing gut microbiota, depression, and IBS. Mediation effects were assessed by examining the indirect pathway of gut microbiota → depression → IBS. ResultsTwo-sample MR analysis unveiled a statistically significant causal association (P < 0.05) between specific bacterial group within the gut microbiota, notably p_Actinobacteria(OR = 0.829225), c_Clostridia(OR = 0.798897), s_Desulfovibrio_piger(OR = 1.163912), g_Streptococcus(OR = 1.132735), c_Actinobacteria(OR = 0.829224), and the onset of IBS. In the MVMR analysis, the relationship between depression and IBS was significant across Model 3, Model 7, Model 8, and Model 13 (P < 0.05). Assessment of mediation effects revealed that c_Clostridia and o_Clostridiales indirectly impacted IBS through depression, with masking effect ratios of 168.46 % and 168.44 %, respectively. ConclusionThese findings underscore a resilient causal association between the composition of gut microbiota and the initiation of IBS. Furthermore, depression serves as a mediator for particular groups of gut bacteria, thereby contributing to the development of IBS. These observations imply that interventions targeting mental health may potentially alleviate the risk of IBS onset attributable to adverse configurations of gut microbiota.

Deciphering the brain-gut axis: elucidating the link between cerebral cortex structures and functional gastrointestinal disorders via integrated Mendelian randomization.

Observational studies have suggested associations between functional gastrointestinal disorders (FGIDs) and variations in the cerebral cortex. However, the causality of these relationships remains unclear, confounded by anxiety and depression. To clarify these causal relationships and explore the mediating roles of anxiety and depression, we applied univariate, multivariable, and mediation Mendelian randomization (MR) analyses. We utilized genome-wide association study (GWAS) summary data from the FinnGen database and the ENIGMA consortium, identifying genetic variants associated with irritable bowel syndrome (IBS), functional dyspepsia (FD), and cerebral cortex structures. Data on anxiety and depression came from FinnGen and a large meta-analysis. Utilizing a bidirectional univariate MR approach, we explored correlations between FD, IBS, and cortex variations. Then, independent effects were assessed through multivariable MR. A meta-analysis of these results, incorporating data from two cohorts, aimed to increase precision. We also explored the potential mediating roles of anxiety and depression. Our findings indicate a negative causal correlation between FD and the thickness of the rostral anterior cingulate cortex (rACC) across both global and regional adjustments (β = -0.142, 95% confidence interval (CI): -0.209 to-0.074, P.FDR = 0.004; β = -0.112, 95%CI: -0.163 to-0.006, P.FDR = 0.003) and a positive causal correlation with the globally adjusted thickness of the superior frontal gyrus (SFG) (β = 0.107, 95%CI: 0.062 to 0.153, P.FDR = 0.001). The causal correlation with the rACC persisted after multiple variable adjustments (β = -0.137, 95% CI: -0.187 to-0.087, P.FDR = 1.81 × 10-5; β = -0.109, 95%CI: -0.158 to-0.06, P.FDR = 0.002). A significant causal association was found between globally adjusted surface area of the caudal anterior cingulate cortex (cACC) and IBS (odds ratio = 1.267, 95%CI: 1.128 to 1.424, P.FDR = 0.02). The analysis showed that neither anxiety nor depression mediated the relationship between FGIDs and cerebral cortex structures. Our research provides significant MR evidence of a bidirectional causal relationship between FGIDs and the cerebral cortex structures. This evidence not only confirms the two-way communication along the brain-gut axis but also illuminates the underlying pathophysiology, paving the way for identifying potential therapeutic approaches.

Causal associations between platelet count, alcohol consumption, and the risk of liver hepatocellular carcinoma based on a Mendelian randomization study.

Liver hepatocellular carcinoma (LIHC) exhibits a multifactorial etiology, insidious onset, and a significantly low 5-year survival rate. We aimed to evaluate the causal impact of exposure factors (Alzheimer's disease, platelet count, ambidextrousness, cigarettes smoked per day, alcohol consumption, and endocarditis) on the risk of LIHC using a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms (SNPs) strongly associated with Alzheimer's disease, platelet count, ambidextrousness, daily cigarette consumption, alcohol intake, and endocarditis were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). Genetic summary statistics for LIHC came from a GWAS that included 168 cases and 372,016 controls of European individuals. Multivariable MR analyses were performed to find the causal association between 6 exposure factors and LIHC risk. The inverse-variance weighted (IVW)-MR was employed as the primary analysis, and the MR-Egger regression, LASSO regression, and weighted Median approaches were performed as complementary analyses. Multivariable MR analysis showed causal association between Alzheimer's disease [Odds ratio (OR) = 0.9999, 95% confidence intervals (CI) = 0.9998-0.9999, p = 0.0010], platelet count (OR = 0.9997, 95% CI = 0.9995-0.9999, p = 0.0066), alcohol consumption (OR = 0.9994, 95% CI = 0.9990-0.9999, p = 0.0098) and the LIHC outcome. After IVW-MR, MR-Egger and LASSO tests, the results are still significant. Next, we used different MR Methods to analyze platelet count, alcohol consumption, and Alzheimer's disease separately. Moreover, both funnel plots and MR-Egger intercepts provided compelling evidence to refute the presence of directional pleiotropy in the association between platelet count, alcohol consumption, Alzheimer's disease and the risk of LIHC. The IVW-MR analysis revealed a significant causal association between an elevated platelet count and a reduced risk of LIHC (OR = 0.9996, 95% CI= 0.9995-0.9998, p = 0.0005). Similarly, the analysis of weighted median revealed a negative correlation between platelet count and the risk of LIHC (OR = 0.9995, 95% CI = 0.9993-0.9999; p = 0.0160). Conversely, we observed a positive causal effect of alcohol consumption on the incidence of LIHC (OR = 1.0004, 95% CI = 0.9999-1.0009). However, no significant causal relationship was found between alcohol assumption, Alzheimer's disease, and LIHC susceptibility. A significant causal relationship exists between platelet count, alcohol consumption, Alzheimer's disease, and an increased risk of LIHC. The study presents compelling evidence for a genetically predicted decreased susceptibility to LIHC based on platelet count. The research implies that elevated platelet count may serve as a protective mechanism against LIHC. These findings may inform clinical strategies for LIHC prevention.

Juvenile idiopathic arthritis and primary ovarian failure: a two-sample Mendelian randomization analysis in a mixed-gender cohort.

The causal relationship between juvenile idiopathic arthritis (JIA) and primary ovarian failure (POF) remains uncertain. To elucidate this relationship, we employed a two-sample Mendelian randomization analysis. The single nucleotide polymorphisms (SNPs) associated with JIA were obtained from a previously published genome-wide association study (GWAS), while the pooled data for POF originated from the FinnGen consortium. The study populations consisted exclusively of individuals of European descent. In our Mendelian randomization analysis, we performed inverse-variance weighted analysis, weighted-median analysis, weighted-mode analysis and Mendelian randomization-Egger regression analysis, supplemented by sensitivity analyses to validate the accuracy and robustness of the findings. The IVW (OR = 1.23, 95% CI 1.06-1.43; P = 0.007) and weighted median (OR = 1.25, 95% CI 1.06-1.47; P = 0.009), along with sensitivity analysis validation, provide compelling evidence of a significant causal association between JIA and POF. The study revealed a significant causal association between genetically predicted JIA and POF, indicating that JIA significantly elevates the risk of developing POF. Therefore, it is recommended to implement screening for premature ovarian failure in women diagnosed with JIA.

Oxidative stress and neurodegenerative diseases: a bidirectional Mendelian randomization study.

Oxidative stress (OS) has been linked to neurodegenerative diseases in numerous epidemiological studies; however, whether it is a pathogenesis or a downstream factor remains controversial. A two-sample bidirectional Mendelian randomization (MR) analysis was implemented to examine evidence of causality of 15 OS injury markers with 3 major neurodegenerative diseases using available genome-wide association studies statistics. As a main approach, inverse-variance weighted (IVW) analysis was performed. The weighted-median (WM) analysis was used to validate the relationship. In order to investigate the existence of horizontal pleiotropy and correct the IVW estimate, the Radial MR approach was applied. To gauge the consistency and robustness of the findings, several sensitivity and pleiotropy analyses were used. For this analysis, p < 0.05 indicates a nominally causal association; according to the Bonferroni correction test, p < 0.0011 indicates a statistically significant causal association. Via IVW and WM, in directional MR, it was genetically predicted that zinc was nominally causally correlated with the risk of Parkinson's disease but not after Bonferroni correction test; alpha-tocopherol was nominally causally correlated with the risk of Amyotrophic lateral sclerosis (ALS) but not after Bonferroni correction test; furthermore, in reverse MR, it was genetically predicted that Alzheimer's disease was causally correlated with uric acid but not after Bonferroni correction test. These above findings were stable across sensitivity and pleiotropy analyses. Based on the current study, there is no authentic genetic causal association between OS biomarkers and neurodegenerative diseases. The complex relationship is required to be confirmed in future experimental research.

Exploring the causal association between genetically determined circulating metabolome and hemorrhagic stroke.

Hemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects. We assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders. We finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40-0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08-0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02-4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09-0.77, PMVMR = 0.015) with significant causal relation to HS. We demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.

Deciphering the causal relationship between plasma and cerebrospinal fluid metabolites and glioblastoma multiforme: a Mendelian Randomization study.

Glioblastoma Multiforme (GBM) is one of the most aggressive and fatal brain cancers. The study of metabolites could be crucial for understanding GBM's biology and reveal new treatment strategies. The GWAS data for GBM were sourced from the FinnGen database. A total of 1400 plasma metabolites were collected from the GWAS Catalog dataset. The cerebrospinal fluid (CSF) metabolites data were collected from subsets of participants in the WADRC and WRAP studies. We utilized the inverse variance weighting (IVW) method as the primary tool to explore the causal relationship between metabolites in plasma and CSF and glioblastoma, ensuring the exclusion of instances with horizontal pleiotropy. Additionally, four supplementary analytical methods were applied to reinforce our findings. Aberrant results were identified and omitted based on the outcomes of the leave-one-out sensitivity analysis. Conclusively, a reverse Mendelian Randomization analysis was also conducted to further substantiate our results. The study identified 69 plasma metabolites associated with GBM. Of these, 40 metabolites demonstrated a significant positive causal relationship with GBM, while 29 exhibited a significant negative causal association. Notably, Trimethylamine N-oxide (TMAO) levels in plasma, not CSF, were found to be a significant exposure factor for GBM (OR = 3.1627, 95% CI = (1.6347, 6.1189), P = 0.0006). The study did not find a reverse causal relationship between GBM and plasma TMAO levels. This research has identified 69 plasma metabolites potentially associated with the incidence of GBM, among which TMAO stands out as a promising candidate for an early detectable biomarker for GBM.

Association between human blood metabolites and cerebral cortex architecture: evidence from a Mendelian randomization study.

Dysregulation of circulating metabolites may affect brain function and cognition, associated with alterations in the cerebral cortex architecture. However, the exact cause remains unclear. This study aimed to determine the causal effect of circulating metabolites on the cerebral cortex architecture. This study utilized retrieved data from genome-wide association studies to investigate the relationship between blood metabolites and cortical architecture. A total of 1,091 metabolites and 309 metabolite ratios were used for exposure. The brain cortex surface area and cortex thickness were selected as the primary outcomes in this study. In this study, the inverse variance weighting method was used as the main analytical method, complemented by sensitivity analyses that were more robust to pleiotropy. Furthermore, metabolic pathway analysis was performed via MetaboAnalyst 6.0. Finally, reverse Mendelian randomization (MR) analysis was conducted to assess the potential for reverse causation. After correcting for the false discovery rate (FDR), we identified 37 metabolites and 9 metabolite ratios that showed significant causal associations with cortical structures. Among these, Oxalate was found to be most strongly associated with cortical surface area (β: 2387.532, 95% CI 756.570-4018.495, p = 0.037), while Tyrosine was most correlated with cortical thickness (β: -0.015, 95% CI -0.005 to -0.025, p = 0.025). Furthermore, pathway analysis based on metabolites identified six significant metabolic pathways associated with cortical structures and 13 significant metabolic pathways based on metabolite ratios. The identified metabolites and relevant metabolic pathways reveal potential therapeutic pathways for reducing the risk of neurodegenerative diseases. These findings will help guide health policies and clinical practice in treating neurodegenerative diseases.

Causality of Helicobacter pylori infection on eosinophilic esophagitis and potential pathogenesis: a Mendelian randomization study.

Observational studies have indicated a possible connection between Helicobacter pylori (H. pylori) infection and eosinophilic esophagitis (EoE), but their causal relationship has yet to be established. To investigate the causal associations between H. pylori infection and EoE, we performed a Mendelian randomization (MR) analysis. Firstly, we conducted both univariable and multivariable Mendelian randomization (MR) analyses. Furthermore, a two-step MR was carried out to ascertain the potential underlying pathways of these associations, particularly the involvement of inflammatory cytokines. We employed the inverse-variance weighted (IVW) method as the main analysis in our MR study. To enhance the credibility of the results, we also conducted several sensitivity analyses. Our study demonstrated a noteworthy correlation between genetically predicted anti-H. pylori IgG antibody levels and a reduced risk of EoE (OR=0.325, 95% CI=0.165-0.643, P value=0.004, adj p value=0.009). No significant causal associations were detected between other H. pylori antibodies and EoE in our study. When it comes to multivariable MR analysis controlling for education attainment, household income, and deprivation individually, the independent causal impact of anti-H. pylori IgG on EoE persisted. Surprisingly, the two-step MR analysis indicated that inflammatory factors (IL-4, IL-5, IL-13, IL-17, and IFN-γ) did not appear to mediate the protective effect of H. pylori infection against EoE. Findings suggested that among the range of H. pylori-related antibodies, anti-H. pylori IgG antibody is the sole causal factor associated with protection against EoE. Certain inflammatory factors may not be involved in mediating this association. These findings make a significant contribution to advancing our understanding of the pathogenesis of EoE and its evolving etiology.

Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study

BackgroundRecent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes.MethodsPublished data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium’s genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD.ResultsWe chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005–1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy’s effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973–1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658–1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941–1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035).ConclusionIn this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Dietary factors and Alzheimer’s disease risk: a Mendelian randomization study

BackgroundPrior observational research has investigated the association between dietary patterns and Alzheimer’s disease (AD) risk. Nevertheless, due to constraints in past observational studies, establishing a causal link between dietary habits and AD remains challenging.MethodsMethodology involved the utilization of extensive cohorts sourced from publicly accessible genome-wide association study (GWAS) datasets of European descent for conducting Mendelian randomization (MR) analyses. The principal analytical technique utilized was the inverse-variance weighted (IVW) method.ResultsThe MR analysis conducted in this study found no statistically significant causal association between 20 dietary habits and the risk of AD (All p > 0.05). These results were consistent across various MR methods employed, including MR-Egger, weighted median, simple mode, and weighted mode approaches. Moreover, there was no evidence of horizontal pleiotropy detected (All p > 0.05).ConclusionIn this MR analysis, our finding did not provide evidence to support the causal genetic relationships between dietary habits and AD risk.

Multidimensional plasma lipid composition and its causal association with type 2 diabetes mellitus: A Mendelian randomization study

Background and aimRecent research extends our knowledge of plasma lipid species, building on established links between serum lipid levels and Type 2 Diabetes Mellitus (T2DM) risk. Identifying the causal roles of these lipid species is key to improving T2DM risk assessment. Methods and resultsThis study employs Mendelian randomization (MR) to investigate the causal relationship between 179 lipid species across 13 lipid categories and T2DM. Summary-level data were sourced from genome-wide association studies. The primary analytical methods included the inverse variance weighted (IVW) approach and the Wald ratio, complemented by a series of sensitivity analyses to ensure the robustness of results. The IVW analysis reveals a significant causal association between elevated levels of ceramide (d40:2) (OR = 1.071, 95% CI 1.034–1.109, P = 1.36 × 10−4), sphingomyelin (d38:1) (OR = 1.052, 95% CI 1.028–1.077, P = 1.80 × 10−5), and triacylglycerol (56:8) (OR = 1.174, 95% CI 1.108–1.243, P = 4.65 × 10−8), and an increased risk of T2DM. Conversely, Wald ratio analysis indicates that higher levels of phosphatidylcholine (O-16:1_16:0) (OR = 0.928, 95% CI 0.892–0.966, P = 2.37 × 10−4), phosphatidylcholine (O-16:1_20:4) (OR = 0.932, 95% CI 0.897–0.967, P = 2.37 × 10−4), and phosphatidylcholine (O-18:2_20:4) (OR = 0.872, 95% CI 0.812–0.935, P = 1.24 × 10−4) are significantly associated with a reduced risk of T2DM. Furthermore, suggestive causal evidence for 22 additional lipid species was identified. ConclusionsThis MR study establishes a causal relationship between specific lipid classes in modulating the risk of T2DM. It offers new insights for risk assessment and potential therapeutic targets in T2DM.

Do Drug Cost Containment Measures in India Increase Affordability of Cancer Drugs? Evidence from Spending on and Cost of Cancer Medicines

The article examines the drug pricing policy and cost containment measures in India by drawing on the data of spending on and price variations of cancer drugs. Results show that medicines held the highest share in the out-of-pocket (OOP) cancer medical expenditure in private and public sectors, and it was more pronounced for private sector and in outpatient care. Medicine expenditure has a positive and significant causal association to OOP medical expenditure of cancer patients even when other medical costs, type of care and socio-economic backgrounds are controlled for. Further, there were significant price variations for recently approved anticancer medicines across brands, which are under and outside price control. The results confirm the ineffectiveness of price control measures for cancer drugs under market-based pricing policy and the inadequacy of existing risk protection measures in India. This calls for the adoption of appropriate cost containment measures, which include expanding the scope of all forms, types and severities of cancer and anticancer medications under health insurance and adoption of a uniform treatment protocol across private and public sectors.

PM2.5 associates with blood pressure: a Mendelian randomization analysis

ABSTRACT The relationship between fine particulate matter (PM2.5) and blood pressure (BP) is a controversial issue. We conducted a two-sample Mendelian randomization (MR) analysis and identified 58 genome-wide significant single-nucleotide polymorphisms associated with PM2.5 as instrument variables. Inverse-variance weighted (IVW) was used as the primary analysis approach. MR-Egger, weighted median, simple model, and weighted model methods were selected for quality control. We found a significant negative causal association of higher genetically predicted PM2.5 levels with lower systolic BP (SBP), while no causal relationship was identified between PM2.5 and diastolic BP (DBP). For each 1 standard deviation increase in genetically predicted PM2.5 levels, the beta value (95% CI) of SBP was -0.14 (-0.25, -0.03) for IVW (p=0.02), and -0.13 (-0.22, -0.04) for weighted median (p=0.005). Increased PM2.5 concentrations can lead to decreased SBP levels. Our findings provided novel insights into the controversial topic on the causal relationship between PM2.5 and BP.

Causal roles of gut microbiota in cholangiocarcinoma etiology suggested by genetic study.

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with poor prognosis. Previous studies have implicated the gut microbiota in CCA, but evidence for causal mechanisms is lacking. To investigate the causal relationship between gut microbiota and CCA risk. We performed a two-sample mendelian randomization study to evaluate potential causal associations between gut microbiota and CCA risk using genome-wide association study summary statistics for 196 gut microbial taxa and CCA. Genetic variants were used as instrumental variables. Multiple sensitivity analyses assessed result robustness. Fifteen gut microbial taxa showed significant causal associations with CCA risk. Higher genetically predicted abundance of genus Eubacteriumnodatum group, genus Ruminococcustorques group, genus Coprococcus, genus Dorea, and phylum Actinobacteria were associated with reduced risk of gallbladder cancer and extrahepatic CCA. Increased intrahepatic CCA risk was associated with higher abundance of family Veillonellaceae, genus Alistipes, order Enterobacteriales, and phylum Firmicutes. Protective effects against CCA were suggested for genus Collinsella, genus Eisenbergiella, genus Anaerostipes, genus Paraprevotella, genus Parasutterella, and phylum Verrucomicrobia. Sensitivity analyses indicated these findings were reliable without pleiotropy. This pioneering study provides novel evidence that specific gut microbiota may play causal roles in CCA risk. Further experimental validation of these candidate microbes is warranted to consolidate causality and mechanisms.

Possible Causal Association between Type 2 Diabetes and Glycaemic Traits in Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomisation Study.

Existing literature suggests a controversial relationship between type 2 diabetes mellitus (T2D) and glaucoma. This study aimed to examine the potential causal connection between T2D and glycaemic traits (fasting glucose [FG] and glycated haemoglobin [HbA1c] levels) as exposures to primary open-angle glaucoma (POAG) in multi-ethnic populations. Single-nucleotide polymorphisms associated with exposure to T2D, FG, and HbA1c were selected as instrumental variables with significance (p < 5.0 × 10-8) from the genome-wide association study (GWAS)-based meta-analysis data available from the BioBank Japan and the UK Biobank (UKB). The GWAS for POAG was obtained from the meta-analyses of Genetic Epidemiology Research in Adult Health and Aging and the UKB. A two-sample Mendelian randomisation (MR) study was performed to assess the causal estimates using the inverse-variance weighted (IVW) method, and MR-Pleiotropy Residual Sum and Outlier test (MR-PRESSO). Significant causal associations of T2D (odds ratio [OR] = 1.05, 95% confidence interval [CI] = [1.00-1.10], p = 0.031 in IVW; OR = 1.06, 95% CI = [1.01-1.11], p = 0.017 in MR-PRESSO) and FG levels (OR = 1.19, 95% CI = [1.02-1.38], p = 0.026 in IVW; OR = 1.17, 95% CI = [1.01-1.35], p = 0.041 in MR-PRESSO) with POAG were observed, but not in HbA1c (all p > 0.05). The potential causal relationship between T2D or FG and POAG highlights its role in the prevention of POAG. Further investigation is necessary to authenticate these findings.

Protective effect of higher free thyroxine levels within the reference range on biliary tract cancer risk: a multivariable mendelian randomization and mediation analysis.

Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC. Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis. The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC). The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process.

Causal association between gut microbiomes and different types of aneurysms: a Mendelian randomization study.

Previous studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear. A two-sample Mendelian randomization was conducted to investigate whether gut microbiomes have a causal effect on the risk of intracerebral aneurysm (IA), thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA), and aortic aneurysm (AA). Single nucleotide polymorphisms (SNPs) smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. We used inverse-variance weighted (IVW) test as the primary method for the evaluation of causal association. MR-Egger, weighted median, weighted mode, and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods were conducted for sensitive analysis. The p-value was adjusted by the false discovery rate (FDR) which adjust the results of multiple comparisons, a p < 0.05 and q < 0.1 was considered a significant causal association. Additionally, a p < 0.05 and q > 0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality. The phylum Firmicutes (OR = 0.62; 95% CI, 0.48-0.81), class Lentisphaeria (OR = 0.75; 95% CI, 0.62-0.89), and order Victivallales (OR = 0.75; 95% CI, 0.62-0.89) have a causal protective effect on the risk of AAA. Additionally, class Verrucomicrobia, class Deltaproteobacteria, order Verrucomicrobiale, family Verrucomicrobiacea, genus Eubacterium rectale group, genus Akkermansia, and genus Clostridium innocuum group were negatively associated with the risk of different types of aneurysms, whereas class Negativicutes, order Selenomonadales, and genus Roseburia had positive causal association with different types of aneurysms (p < 0.05; q > 0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05). Our MR analysis confirmed the causal association of specific gut microbiomes with AAA, and these microbiomes were considered as protective factors. Our result may provide novel insights and theoretical basis for the prevention of aneurysms through regulation of gut microbiomes.

Potential Causal Association between C-Reactive Protein Levels in Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study.

Researchers have proposed a possible correlation between age-related macular degeneration (AMD) and inflammation or C-reactive protein (CRP) levels. We investigated the potential causal relationship between CRP levels and AMD. Single-nucleotide polymorphisms (SNPs) associated with CRP exposure were selected as the instrumental variables (IVs) with significance (p < 5 × 10-8) from the genome-wide association study (GWAS) meta-analysis data of Biobank Japan and the UK Biobank. GWAS data for AMD were obtained from 11 International AMD Genomics Consortium studies. An evaluation of causal estimates, utilizing the inverse-variance-weighted (IVW), weighted-median, MR-Egger, MR-Pleiotropy-Residual-Sum, and Outlier tests, was conducted in a two-sample Mendelian randomization (MR) study. We observed significant causal associations between CRP levels and AMD (odds ratio [OR] = 1.13, 95% CI = [1.02-1.24], and p = 0.014 in IVW; OR = 1.18, 95% CI = [1.00-1.38], and p = 0.044 in weight median; OR = 1.31, 95% CI = [1.13-1.52], and p < 0.001 in MR-Egger). The causal relationship between CRP and AMD warrants further research to address the significance of inflammation as a risk factor for AMD.