Bidirectional Mendelian Randomization Study Research Articles

Causal association between diabetes and herpesvirus infections: a bidirectional two-sample mendelian randomization study

Causal association between diabetes and herpesvirus infections: a bidirectional two-sample mendelian randomization study

Insights from bidirectional Mendelian randomization: Evaluating the influence of circulating inflammatory cytokines on prostatitis.

Research on prostatitis has primarily focused on inflammatory cytokines in semen or prostatic secretions, with relatively few studies investigating circulating inflammatory cytokines. To explore the relationship between prostatitis and circulating inflammatory cytokines, this study employed bidirectional two-sample Mendelian randomization (MR) to assess the potential associations between prostatitis and 91 circulating inflammatory cytokines. We performed bidirectional MR to explore causal links between 91 circulating inflammatory cytokines and prostatitis. Data were sourced from 14,824 individuals of European ancestry and the Finngen database for prostatitis. The inverse variance-weighted (IVW) method was the primary tool, complemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO to enhance result robustness. Heterogeneity and pleiotropy evaluations were conducted, and GO/KEGG enrichment analyses were used to explore the biological pathways linked to these inflammatory factors and prostatitis. The MR results revealed that Interleukin-10 receptor A (IL-10RA), Natural Killer Cell Receptor 2B4 (CD244), and urokinase-type plasminogen activator (uPA) were identified as risk factors for prostatitis (IVWIL-10RA: OR = 1.242, 95% CI: 1.043-1.478, P = .015; IVWCD244: OR = 1.143, 95% CI: 1.002-1.305, P = .047; IVWuPA: OR = 1.141, 95% CI: 1.009-1.290, P = .035). Conversely, Interleukin-12B (IL-12B) exhibited a protective effect against prostatitis (IVWIL-12B: OR = 0.909, 95% CI: 0.842-0.981, P = .014). Moreover, reverse MR analysis results indicate that prostatitis decreases plasma levels of chemokine (C-C motif) ligand 23 (CCL23), IL-5, and TNF-related activation-induced cytokine (TRANCE) (IVWCCL23: OR = 0.949, 95% CI: 0.906-0.993, P = .025; IVWIL-5: OR = 0.938, 95% CI: 0.890-0.988, P = .016; IVWTRANCE: OR = 0.947, 95% CI: 0.905-0.992, P = .021). This bidirectional MR study identified potential causal links between 7 circulating inflammatory cytokines and prostatitis, offering insights into its pathogenesis and potential targets for future therapies.

Causal relationship between schizophrenia and five types of dementia: A bidirectional two-sample Mendelian randomization study.

Although observational research indicates an association between schizophrenia and dementia, it is unclear whether the two are causally related. In order to examine the causal relationship between schizophrenia and five types of dementia (all-cause dementia, Alzheimer's disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies), we performed a bidirectional two-sample Mendelian randomization analysis. In this study, pooled statistics of schizophrenia and dementia were obtained from the Large-scale genome-wide association study (GWAS) in individuals of European ancestry. Inverse variance weighted (IVW) was the primary statistical approach used in this Mendelian randomization, to further support our findings, we also used MR-Egger, weighted median, and cML-MA. We also used a number of sensitivity analyses to evaluate pleiotropy and heterogeneity. In the study of the effect of schizophrenia on dementia, findings from the IVW analysis suggested that schizophrenia is associated with an increased risk of all-cause dementia (OR = 1.065, 95%CI: 1.027 ～ 1.104, P = 0.001, FDR-corrected P = 0.003), Alzheimer's disease (OR = 1.029, 95%CI: 1.003 ～ 1.054, P = 0.027, FDR-corrected P = 0.045), and vascular dementia (OR = 1.106, 95%CI: 1.023 ～ 1.197, P = 0.012, FDR-corrected P = 0.029). In the study of the effect of dementia on schizophrenia, no form of dementia assessed in this study was found to be a risk factor for schizophrenia. Our findings suggest that schizophrenia may be a risk factor for all-cause dementia, Alzheimer's disease, and vascular dementia, but no dementia of any kind was found to be a risk factor for schizophrenia. Our study provides insights into the potential genetic relationship between schizophrenia and dementia.

Genetic association of social participation with cognitive function: A bidirectional Mendelian randomization study.

BackgroundCognitive decline poses a significant challenge in aging societies. While some studies suggest that active social participation mitigates cognitive decline, others present conflicting findings.ObjectiveThis bidirectional two-sample Mendelian randomization (MR) study aimed to elucidate the causal relationship between social participation and cognitive function.MethodsThe cognitive performance dataset (n = 257,841) was used as the discovery sample, while cognitive function (n = 22,593) and Alzheimer's disease (AD) datasets (n = 394,705) served as replication samples and proxies for severe cognitive decline. Inverse variance weighting was the primary analytical method, supplemented by weighted median, MR-Egger, MR.RAPS, MR-PRESSO, and maximum likelihood methods for sensitivity analyses.ResultsSocial participation in sports club or gym (β = 0.09, 95% CI: 0.05 to 0.14, p < 0.001), religious group (β = 0.11, 95% CI: 0.08 to 0.14, p < 0.001) and other group activity (β = 0.06, 95% CI: 0.03 to 0.09, p < 0.001) reduced the risk of cognitive decline, while pub or social club (β = -0.06, 95% CI: -0.1 to -0.02, p = 0.005) and social inactivity (β = -0.05, 95% CI: -0.09 to -0.01, p = 0.017) accelerated cognitive decline. Improved cognitive performance promoted participation in beneficial activities and reduced pub or social club participation. Additionally, AD motivated visits to pub or social club (OR = 1.01, 95% CI: 1.00 to 1.03, p = 0.011).ConclusionsSpecific types of social participation may protect against cognitive decline, offering evidence for targeted interventions to prompt cognitive health in aging populations.

Causal associations between epigenetic age and thromboembolism: a bi-directional two-sample Mendelian randomization study

BackgroundThromboembolism is one of the most prevalent cardiovascular conditions affecting the elder population. The associations between epigenetic aging and thromboembolism risks remain incompletely elucidated. Through Mendelian randomization (MR), this research seeks to assess the causal links between genetically determined epigenetic aging factors and thromboembolism.ResultsGenetic variants were extracted from genome-wide association studies (GWAS) under stringent threshold as instrumental variables (IVs). Bi-directional two-sample MR analyses were conducted to determine the direction of causal associations. We employed the inverse variance weighted (IVW), weighted median, weighted mode and MR Egger to estimate the causal effect, with sensitivity analyses such as Cochran’s Q tests, MR-PRESSO and leave-one-out performed to avoid potential heterogeneity and pleiotropy. Our MR analysis revealed a causal association between intrinsic epigenetic age acceleration and deep vein thrombosis of lower extremities (IVW: OR 0.963, 95% CI 0.934–0.992, P = 0.014), and between the genetically determined levels of plasminogen activator inhibitor-1 and other arterial embolism and thrombosis (IVW: OR 1.000, 95% CI 1.000–1.0005, P = 0.029). Causality was also identified between the genetically predicted levels of FGF23 and other arterial embolism and thrombosis (IVW: OR: 1.661, 95% CI 1.051–2.624, P = 0.029) and arterial embolism and thrombosis of lower extremity artery (IVW: OR 1.68, 95% CI 1.031–2.725, P = 0.037). Moreover, bi-directional MR showed reverse effects between portal vein thrombosis and PhenoAge (IVW: OR 0.871, 95% CI 0.765–0.992, P = 0.037) and between venous thromboembolism and GrimAge (IVW: OR 1.186, 95% CI 1.048–1.341, P = 0.007). Sensitivity analysis using Cochran’s Q tests, MR-PRESSO and leave-one-out excluded the influence of heterogeneity, horizontal pleiotropy, and outliers.ConclusionOur results identified a causal association between genetically predicted epigenetic aging factors and thromboembolism. The findings highlight the necessity for further exploration into the underlying etiology of thromboembolism.

Causal relationship between inflammatory cytokines and posttraumatic stress disorder: a Mendelian randomization study and potential mechanism analysis

ABSTRACT Background: Post-traumatic stress disorder (PTSD) is a complex condition linked to inflammation. The causality between inflammatory cytokines and PTSD risk remains unclear. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) study using genome-wide association study (GWAS) data from 41 inflammatory cytokines and PTSD. Additional analyses included differential gene expression, protein–protein interaction, and functional enrichment to explore underlying mechanisms. Results: MR analysis indicated that higher levels of stem cell factor (SCF) and interleukin-4 (IL-4) are associated with a reduced risk of PTSD. Genes POGZ and LRIG2 were identified as mediators, implicated in the TGF-beta signalling pathway. Conclusion: Our findings suggest a protective role of certain cytokines against PTSD and highlight potential molecular mediators. This knowledge could inform future therapeutic strategies for PTSD.

Causal associations between iron deficiency anemia and digestive system cancers: evidence from a bidirectional two-sample Mendelian randomization study

Background & AimsIron deficiency anemia (IDA) is associated with digestive system cancers (DSCs), but the causal relationship is poorly understood. This two-sample bidirectional Mendelian randomization (MR) study investigated the causal association between IDA and five types of DSCs.MethodsThis study pooled data from a genome-wide association study of IDA (6,087 cases and 211,115 controls of European ancestry) and DSCs. IVW, weighted median, weighted mode, and MR-Egger regression were used to assess causal associations between IDA and DSCs. Sensitivity analysis included Cochran’s Q test for heterogeneity, MR-PRESSO for pleiotropy, and leave-one-out method for robustness.ResultsThe MR analysis used 12 single-nucleotide polymorphisms (SNPs) associated with IDA as instrumental variables (IVs). In contrast, the reverse MR analysis used 20 SNPs associated with the five types of DSC as IVs. Genetic predictions revealed no significant association between IDA and the risk of DSCs: (odds ratio [OR]: 1.00; 95% confidence interval [CI] [0.76, 1.31]; P = 0.979), esophageal (OR: 0.94; 95% CI [0.67, 1.31]; P = 0.699), pancreatic (OR: 1.14; 95% CI [0.68, 1.92]; P = 0.615), liver (OR: 1.12; 95% CI [0.51, 2.47]; P = 0.776), and stomach (OR: 1.04; 95% CI [0.71, 1.54]; P = 0.830) cancers. Reverse MR also indicated no causal association between DSC and IDA. MR-Egger regression showed minimal heterogeneity impact except for colorectal cancer (heterogeneity P = 0.002). MR-PRESSO identified no outliers.ConclusionThe present MR analysis shows no causal associations between IDA and the risk of DSCs.

Causal relationship between graves' disease and mental disorders: A bidirectional Mendelian randomization study.

Causal relationship between graves' disease and mental disorders: A bidirectional Mendelian randomization study.

Causal relationship between circulating inflammatory proteins and atherosclerosis: a bidirectional Mendelian randomization study and meta-analysis.

Causal relationship between circulating inflammatory proteins and atherosclerosis: a bidirectional Mendelian randomization study and meta-analysis.

Association Between Inflammatory Cytokines and Refractive Errors: A Bidirectional Mendelian Randomization Study.

This investigation aimed to elucidate the causal role of inflammatory cytokines in the risk of developing refractive errors. Genetic variants previously associated with inflammatory cytokines served as instrumental variables in genome-wide association studies (GWASs) of European ancestry. Bidirectional two-sample Mendelian randomization (MR) analyses were conducted using summary data from GWAS meta-analyses. Rigorous sensitivity analyses were performed to validate the reliability of the MR results. We found that, for every unit increase in interleukin 1 receptor antagonist (IL1RA) and interleukin 2 (IL2), there was a corresponding decrease in the prevalence of myopic refractive errors by 0.235 (95% confidence interval [CI], 0.050-0.419 for fixed effects; 95% CI, 0.125-0.345 for random effects) and 0.132 (95% CI, 0.032-0.231 for fixed effects; 95% CI, 0.044-0.220 for random effects), respectively. No substantial causal associations were observed for IL1α, IL1β, IL12p70, or monocyte chemoattractant protein 1 (MCP1) with refractive errors. Conversely, reverse MR analyses failed to indicate a causal influence of refractive errors on IL1RA and IL2. The present study offers evidence for a causal link between inflammatory cytokines and refractive errors, which could have significant implications for the early detection, surveillance, and management of refractive errors. Our study underscores the importance of IL1RA and IL2 in the prevention and management of refractive errors, suggesting the feasibility of strategies for early identification, continuous surveillance, and the deployment of focused therapeutic approaches.

Causal associations of brain imaging-derived phenotypes and intracranial aneurysm: a bidirectional Mendelian Randomization study.

Causal associations of brain imaging-derived phenotypes and intracranial aneurysm: a bidirectional Mendelian Randomization study.

Major depressive disorder and the development of cerebral small vessel disease: A Mendelian randomization study.

Major depressive disorder and the development of cerebral small vessel disease: A Mendelian randomization study.

A Bidirectional Two-Sample Mendelian Randomization Study of Genetic Causality Between Vitamin D Levels and Pemphigus

A Bidirectional Two-Sample Mendelian Randomization Study of Genetic Causality Between Vitamin D Levels and Pemphigus

Associations Between the Gut Microbiota and Its Related Metabolic Pathways and Uveitis: A Bidirectional Two-Sample Mendelian Randomization Study.

Associations Between the Gut Microbiota and Its Related Metabolic Pathways and Uveitis: A Bidirectional Two-Sample Mendelian Randomization Study.

Causal relationship between molecular markers of biological aging and orthopedic diseases: A two-sample bidirectional Mendelian randomization study

Causal relationship between molecular markers of biological aging and orthopedic diseases: A two-sample bidirectional Mendelian randomization study

Mitochondrial DNA Copy Number as a Hidden Player in the Progression of Multiple Sclerosis: A Bidirectional Two-Sample Mendelian Randomization Study.

The relationship between mitochondrial DNA copy number (mtDNA-CN) and multiple sclerosis (MS) progression remains unclear, as previous observational studies have reported conflicting results. This study aimed to clarify the association between mtDNA-CN and MS progression using a bidirectional two-sample Mendelian randomization (MR) approach. MR analyses were conducted using the latest summary statistics from genome-wide association studies (GWAS) on mtDNA-CN and MS progression. Single-nucleotide polymorphisms (SNPs) associated with mtDNA-CN were extracted from 383,476 participants of European ancestry in the UK Biobank, while SNPs associated with MS severity were obtained from the International Multiple Sclerosis Genetics Consortium (IMSGC), comprising 12,584 cases of European ancestry. The inverse variance weighted (IVW) method was used as the primary analysis. Potential heterogeneity and pleiotropy were evaluated, and sensitivity analyses were performed to ensure the robustness of the results. The forward MR analysis using the IVW method revealed no significant association between mtDNA-CN and MS progression (P = 0.487). However, reverse MR analysis identified a causal association between MS progression and mtDNA-CN (β = - 0.010, 95% CI = - 0.019 to - 0.001, P = 0.036). No evidence of heterogeneity or horizontal pleiotropy was found in the analyses. Sensitivity analyses yielded consistent results. Our findings suggest that MS progression may causally influence mtDNA-CN, highlighting the crucial role of mitochondria in the pathophysiology of MS. However, further research is needed to confirm mtDNA-CN as a reliable biomarker and a deeper understanding of the molecular mechanisms is necessary to develop targeted therapeutic interventions.

Causal effect between telomere length and thirteen types of cancer in Asian population: a bidirectional Mendelian randomization study

BackgroundThe relationship between leukocyte telomere length (LTL) and the risk of developing various cancers has always been controversial and predominantly focused on European populations. Hence, Mendelian randomization (MR) was applied to the Asian population to explore the causal relationships between LTL and the risk of developing various cancers.MethodsWe explored the causal connection between LTL and the risk of developing thirteen types of cancer in Asian populations using freely available genetic variation data. The primary analytical method employed was the inverse variance weighted (IVW) method, complemented by sensitivity and validation analyses. Following Bonferroni correction, P < 0.0038 was considered to indicate statistical significance, and P values ranging from 0.0038 to 0.05 were considered to indicate a nominally significant association.ResultsThe findings indicated significant positive associations between LTL and the risk of developing lung cancer [odds ratio (OR) = 1.6009, 95% confidence interval (CI) 1.3056–1.9629, P = 6.08 × 10−6] and prostate cancer (OR = 1.4200, 95% CI 1.1489–1.7550, P = 0.0012). Additionally, there was a nominally significant association between LTL and the risk of developing hematological malignancy (OR = 1.5119, 95% CI 1.0810–2.1146, P = 0.0157). No statistically significant relationships between LTL and the risk of developing the other ten kinds of cancer were detected. No causal link between the risk of developing various cancers and LTL was discovered.ConclusionsAsians with longer telomeres are more prone to developing lung and prostate cancer. There is also a nominally significant association between longer telomeres and the risk of developing hematological malignancy.

Bidirectional Mendelian Randomization analysis of iron status and uremia: no evidence of a causal relationship

Iron status and uremia have been linked, but the causality remains ambiguous. This bidirectional study aimed to explore the causal association between genetically predicted iron status and uremia. Utilizing summary data from genome-wide association studies (GWAS) of iron status and uremia, a two-sample Mendelian Randomization (MR) design was employed. Iron status was assessed through serum iron (SI), serum ferritin (SF), total iron-binding capacity (TIBC), and transferrin saturation (TS), while uremia included renal failure and dialysis. The primary analysis was conducted using the Inverse Variance Weighted (IVW) method. Additional MR evaluation included the weighted median, weighted mode, simple mode, and MR-Egger regression methods. Sensitivity analysis included MR-Egger for pleiotropy, MR-PRESSO for detecting outliers, Cochran’s Q test for heterogeneity, and leave-one-out analysis for robustness. Genetically determined iron status did not have a causal effect on the risk of uremia (renal failure or dialysis). The primary IVW results indicated no statistically significant relationship between iron status and uremia (all p > 0.05). Consistent results were found through various methods. Similarly, there were no significant causal effects of uremia on iron status (all p > 0.05). Heterogeneity was observed in some associations, but pleiotropy was generally not evident. This bidirectional MR study provides no evidence for a causal relationship between genetically predicted iron status and the risk of uremia. These findings challenge prior observational associations and highlight the need for further mechanistic and interventional studies to elucidate the complex interplay between iron metabolism and kidney disease.

Association between stable angina pectoris and gastric cancer: two-sample bidirectional mendelian randomization study.

To explore the possible causal link between stable angina pectoris (SAP) and gastric cancer (GC) through Mendelian randomization analysis. We used data from genome-wide association studies (GWAS) statistical datasets, with SAP and GC screened as relevant instrumental variables for exposure factors, respectively. To evaluate the causal link between SAP and GC, a two-sample bidirectional Mendelian randomization analysis was conducted, leveraging genetic variants as instrumental variables. In addition, effects of horizontal pleiotropy were evaluated using MR-PRESSO and MR-Egger intercept analysis. Sensitivity analysis was performed using Cochran Q test and "leave one out" method. The study showed a significant causal relationship between SAP and GC in the analysis with SAP as the exposure variable (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.69-0.87, p = 0.000027 using inverse variance weighting [IVW]). Sensitivity analysis confirmed the robustness of Mendelian randomization results. In the analysis of GC as an exposure variable, gastric cancer and SAP also showed a significant causal association (OR = 0.87, 95%CI = 0.77-0.98, p = 0.024 using IVW), but sensitivity analysis suggested a significant pleiotropy between instrumental variables (p = 0.0093 using MR-Egger intercept analysis), which cast doubt on the reliability of the study and requires careful interpretation of the results. Existing studies suggest that individuals with SAP may have a lower risk of developing GC. However, the precise causal relationship, particularly regarding whether GC contributes to an increased risk of SAP, remains unclear and warrants further investigation. GC and ischemic heart disease which represented by SAP are both associated with oxidative stress in their pathogenesis. Local tissue-induced mitochondrial autophagy or cellular ferroptosis triggers a systemic response, potentially underlying the negative correlation between GC and SAP. Thus, therapeutic strategies that target the interplay between local tissue and systemic responses in oxidative stress may hold promise for the benefits to patients.

Association between telomere length and psychiatric disorders: a bidirectional Mendelian randomization study.

Observational studies have suggested that shorter telomere length (TL) may be a risk factor for psychiatric disorders. However, whether this association underlie causal effects remains unknown. This study aims to investigate the potential association between TL and psychiatric disorders by conducting a bidirectional Mendelian randomization (MR) study. Summary statistics for TL were obtained from the UK Biobank (n = 472,174), while summary statistics for ten psychiatric disorders were acquired from the Psychiatric Genomics Consortium (PGC). The inverse-variance weighted (IVW) method was used as primary analysis, with the MR-Egger, weighted median, MR-PRESSO, simple mode, and weighted mode approaches were utilized as sensitivity analyses. Our findings indicated a potential association between genetic predisposition to attention deficit hyperactivity disorder (ADHD) and shortened TL (Beta = - 0.039, SE = 0.011, P = 4.00E-04). Additionally, posttraumatic stress disorder (PTSD) may be was potentially associated with TL (Beta = - 0.014, SE = 0.006, P = 0.019). Our findings suggest a potential correlation between ADHD and TL, yet no significant association exists between TL and other psychiatric disorders. Nevertheless, considering the small effect size and the fact that it might have limited practical clinical significance, TL may not function as a biomarker for psychiatric disorders.