Bidirectional Two-sample Mendelian Randomization Study Research Articles

Association of B cells and the risk of Esophageal cancer: a bidirectional two-sample mendelian randomization study.

Currently, research on the role of B cells in esophageal cancer (EC) is limited, and existing studies on their impact are controversial. Therefore, this study was conducted to elucidate the complex causal relationship between B cells and EC, expand the understanding of esophageal cancer immunology. Bidirectional two-sample Mendelian randomization (MR) was performed to assess the causal relationships between 190 B cell phenotypes and EC. To complement the MR analysis, Bayesian Weighted Mendelian Randomization (BWMR) was employed, and sensitivity analyses were conducted to evaluate the robustness of the findings. Positive results were further validated in independent cohorts of esophageal cancer studies. In addition, RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) were utilized for validation, incorporating B cell-related gene expression analysis and functional enrichment analysis to support the MR findings. In the primary analysis, significant causal relationships were observed between 5 B cell types and the risk of EC; the onset of EC was causally linked to 3 B cell phenotypes. Validation in other cohorts revealed that 4 outcomes aligned with the primary analysis, included were CD19 on IgD + CD38-, CD20 on IgD- CD27-, CD20 on IgD- CD38br, and CD38 on PB/PC. Further validation using RNA-seq data showed that CD38 mRNA was significantly overexpressed in EC tissues, whereas CD19 and MS4A1 mRNA levels did not differ significantly between tumor and normal tissues. Functional enrichment analysis revealed that CD19, MS4A1, and CD38 are involved in multiple tumor-related immune pathways, suggesting their pivotal role in regulating the tumor immune microenvironment. Our study suggests a potential connection between B cell phenotypes and EC through bidirectional two-sample MR combined with BWMR analysis, providing a preliminary basis for future research.

The causal relationships between iron status and sarcopenia in Europeans: a bidirectional two-sample Mendelian randomization study.

Previous studies have indicated potential associations between metals, lifestyle factors, and sarcopenia. However, the specific causal relationships between iron status, lifestyle factors, and sarcopenia remain unclear. Therefore, we conducted a bidirectional two-sample Mendelian Randomization (MR) approach to investigate these relationships. The exposure variables included iron status, living alone, coffee intake, alcohol taken with meals, and moderate physical activity, while the outcome variable was sarcopenia, assessed by grip strength in both hands and usual walking pace. We employed the Weighted Median (WM), the Inverse Variance-Weighted (IVW), and other MR methods to explore these problems for analysis. Simultaneously, we conducted a bidirectional MR analysis to assess whether sarcopenia has a reverse causal relationship with internal iron status. In our present research, we found serum iron (P = 0.033), ferritin (P = 0.001), transferrin saturation (P = 0.029) and coffee intake (P = 0.002) revealed a negative trend for sarcopenia, living alone (P = 0.022) and alcohol taken with meal (P = 0.006) showed a opposite trend for sarcopenia. Whereas sarcopenia showed negative trend for ferritin (P = 0.041) and transferrin saturation (P = 0.043), showed the opposite trend for transferrin (P = 0.021). Our study suggested that higher serum iron levels might reduce the risk of sarcopenia. Moreover, living alone and alcohol consumption might increase the sarcopenia risk, while coffee intake and moderate physical activity could reduce the sarcopenia risk.

Genetic determinants of cerebrospinal fluid metabolites and risk of Guillain-Barré syndrome: A bidirectional two-sample Mendelian randomization study.

This study aims to investigate the potential causal relationship between cerebrospinal fluid (CSF) metabolites and Guillain-Barré syndrome (GBS) using a bidirectional two-sample Mendelian randomization (MR) approach. Publicly available summary data from genome-wide association studies (GWAS) were utilized for comprehensive analysis. The CSF metabolite GWAS summary data were extracted from a GWAS conducted by Panyard et al encompassing 338 CSF metabolites in European participants (n = 291). GWAS summary statistics for GBS were obtained from the FinnGen consortium (n = 215,931) comprising European populations. The primary method for MR analysis was the inverse variance weighted method. Various sensitivity analyses were conducted to assess the heterogeneity and pleiotropy of the findings. In the forward MR analysis, we identified a causal relationship between 15 CSF metabolites, including ribitol levels (odds ratio = 3.833, 95% confidence interval: 1.949-7.540, P = 9.87E-05), and the risk of developing GBS. In the reverse MR analysis, we found a causal relationship between GBS and 21 CSF metabolites, including gamma-glutamylphenylalanine levels (odds ratio = 0.934, 95% confidence interval: 0.904-0.966, P = 7.10E-05). No evidence of heterogeneity or horizontal pleiotropy was found in the MR analysis. Our findings suggest that the identified CSF metabolites and metabolic pathways can serve as valuable biomarkers for clinical screening and prevention of GBS. They may also be considered as candidate molecules for future research into the underlying mechanisms and for selecting drug targets.

Causal Effects of Gastroesophageal Reflux on Chronic Rhinosinusitis: A Bidirectional Two-Sample Mendelian Randomization Study.

Observational studies have shown a bidirectional association between gastroesophageal reflux (GER) and chronic rhinosinusitis (CRS) or chronic rhinitis (CR), but it is not clear whether this association is causal. This study was to investigate the causality between GER and CRS or CR using bidirectional two-sample Mendelian randomization (MR) analysis. Using pooled data from large genome-wide association studies (GWAS), genetic loci independently associated with GER, CRS and CR in populations of European and American ancestry were selected as instrumental variables (IVs). The inverse variance weighted (IVW) method was used to analyse the random effects model of MR, and the odds ratio (OR) was used as the evaluation index to explore the bidirectional causality between GER and CRS or CR. Single nucleotide polymorphism (SNP) outliers were detected using MR-pleiotropy Residual Sum and Outliers (MR-PRESSO). The MR-Egger intercept test examined the horizontal pleiotropy of SNPs. The "leave-one-out" sensitivity analysis examined whether MR results were affected by a single SNP. The main results of IVW showed that GER increased the risk of CRS (OR = 1.3795, 95% CI = 1.188-1.603, p < 0.0500) and CR (OR = 1.3941, 95% CI = 1.1671-1.6652, p < 0.0500). The obtained SNPs as IVs for GER, CRS and CR had no significant horizontal pleiotropy, heterogeneity or bias. Regarding the reverse directions, no notable associations could be found. This MR analysis revealed that genetically predicted GER had a causal effect on an increased risk of CRS or CR, but not vice versa. These results have great implications for the management of CRS (especially for refractory CRS) or CR in clinical practice.

Genetical effects of sleep traits on postpartum depression: a bidirectional two-sample Mendelian randomization study

BackgroundPostpartum depression (PPD) is widely recognized as the most prevalent mental health crisis following childbirth and has been linked to sleep disturbances. However, the potential causal relationships between various sleep traits and PPD remain unclear. This study employs a bidirectional two-sample Mendelian randomization (MR) approach to investigate these associations.MethodsThe inverse-variance-weighted method was used to evaluate the causally linked sleep traits on postpartum depression. The weighted median, weighted mode, and MR-Egger were used to estimate the robustness of the inverse-variance-weighted method. The leave-one-out method estimated the sensitivity of the result. Cochran’s Q method was used for the heterogeneous test. The MR-Egger intercept and MR-PRESSO methods detected the horizontal pleiotropy.ResultsWe examined the genetic causal relationships between nine sleep traits and postpartum depression. Sleep apnea syndrome (OR: 1.122; 95%CI: 1.063–1.185; p = 0.000), sleeplessness/insomnia (OR: 1.465; 95%CI: 1.104–1.943; p = 0.008), and frequency of tiredness/lethargy in last 2 weeks (OR: 1.725; 95%CI: 1.345–2.213; p = 0.000) genetically predicted the increased risk of postpartum depression. The reverse Mendelian randomization analysis showed PPD caused sleeplessness/insomnia (β: 0.006; 95%CI: 0.001–0.010; p = 0.016) and frequency of tiredness/lethargy in last 2 weeks (β: 0.007; 95%CI: 0.002–0.011; p = 0.004). The remaining six sleep traits showed no significant association with PPD. There was no heterogeneity or horizontal pleiotropy.ConclusionsGenetic evidence reveals causal relationships between specific sleep traits and PPD, including sleep apnea syndrome, sleeplessness/insomnia, and tiredness. Whether certain sleep health indicators suggest a risk of postpartum depression or sleep issues that are caused by PPD, both may offer insights into the prevention and treatment of PPD.

Evaluating the causal relationship of Levo-carnitine and risk of schizophrenia: a bidirectional two-sample mendelian randomization study

BackgroundSchizophrenia is a debilitating mental disorder affecting about 1% of the global population, characterized by significant cognitive impairments and a strong hereditary component. Carnitine, particularly Levo-carnitine and its derivatives, plays a crucial role in cellular metabolism and mitochondrial function, with evidence suggesting a link between levo-carnitine deficiency and schizophrenia pathology. This study aims to investigate the causal relationship between different subtypes of levo-carnitine and the susceptibility to schizophrenia using Mendelian randomization analysis.MethodsForward Mendelian randomization analysis was conducted using levo-carnitine and its derivatives as exposure and schizophrenia as the outcome. Candidate data were obtained from the Open-GWAS database. Instrumental variables were identified as single nucleotide polymorphisms closely associated with exposure and harmonized with the outcome data after removing confounders and outliers. Mendelian randomization analysis was performed using inverse variance weighting as the primary approach, and sensitivity analysis was conducted to assess the reliability and robustness of the results. Finally, a reverse Mendelian randomization analysis was carried out using the same analytical procedures.ResultsThe Mendelian randomization results indicate a significant negative causal relationship between isovaleryl-levo-carnitine and schizophrenia (P < 0.05), but no significant associations in other groups (P > 0.05). Additionally, the reverse Mendelian randomization analysis did not identify any causal relationship between schizophrenia and levo-carnitine related exposures (P > 0.05). Sensitivity analyses, including pleiotropy and heterogeneity analysis, did not reveal any potential bias in the Mendelian randomization results (P > 0.05).ConclusionThe results suggest that elevated levels of isovaleryl-levo-carnitine may potentially mitigate the risk of developing schizophrenia, highlighting the prospective therapeutic and preventive implications of isovaleryl-levo-carnitine in the clinical management of schizophrenia.

Causal Relationships between Circulating Immune Cell Traits and the Risk of Rheumatoid Arthritis and Osteoarthritis: A Bidirectional Two-Sample Mendelian Randomization Study.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic joint disorders with immunological pathogenesis. However, the causal relationships between circulating immune cells and them remain largely unknown. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to determine their causal relationship. Genome-wide association study summary statistics were extracted from publicly available databases regarding immune cell phenotypes, RA, and OA. MR analysis was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. False discovery rate correction (FDR) was used to reduce the likelihood of type 1 errors. We also conducted MR-Egger intercept tests to evaluate horizontal pleiotropy. After FDR adjustment of the P values for the IVW method, the CD27 expression on memory B cells was negatively related to the risk of RA (P < 0.001), and the human leukocyte antigen (HLA)--DR expression on CD14+ monocytes was negatively related to the risk of OA (P < 0.001). We also found that RA was negatively associated with the expression of HLA-DR on myeloid dendritic cells (P < 0.001), but significant horizontal pleiotropy was observed. Our study demonstrates a causal relationship between specific immune cell traits and RA as well as OA, providing further insight into the role of immune cells in the pathogenesis of these disorders.

The causal association between immune cells and gout: A bidirectional two-sample Mendelian randomization study.

Gout, a metabolic disorder, is increasingly being linked to immune cells. However, the causal relationships between these factors remain unclear. Our study aimed to elucidate the causal relationship between immune cells and gout. Our study used 2-sample Mendelian randomization (MR) to explore the causal relationship between immune cells and gout. It is noteworthy that we utilized 5 methods MR-Egger, weighted median, inverse variance weighted, weighted mode, and simple mode to ensure the reliability of the results. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. After false discovery rate correction (PFDR <0.20), 3 immunophenotypes were identified: one in the B cell panel, one in the regulatory T cells panel, and another in the T lymphocytes, B lymphocytes, Natural Killer cells panel. Among them, 2 immunophenotypes (CD4-CD8-T cell absolute count and CD25 on IgD + CD24 + B cell) increased the risk of developing gout, whereas the other one immunophenotype (CD45RA + CD28- CD8 + T cell %T cell) decreased the risk of gout. Subsequently, we did not observe heterogeneity and horizontal pleiotropy stable in these data through comprehensive sensitivity analyses. Furthermore, we identified some positive results in reverse MR analysis, but after false discovery rate correction (PFDR <0.20), no significant results were detected. Our study revealed causal relationships between immune cells and gout, providing novel insights into the prevention and treatment of gout.

Breast cancer and neoplasms of the thyroid gland: a bidirectional two-sample Mendelian randomization study.

With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90×10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately.

Multi-Ancestry Causal Association between Rheumatoid Arthritis and Interstitial Lung Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Rheumatoid arthritis (RA) is associated with diverse extra-articular manifestations, including interstitial lung disease (ILD). No previous studies have examined the bidirectional relationship between RA and ILD using the Mendelian randomization (MR) analyses. Therefore, we aimed to investigate this subject using a two-sample bidirectional MR method. Methods: We performed bidirectional two-sample MR using summary statistics from genome-wide association studies (GWASs). The data are publicly available, de-identified, and from European (EUR) and East Asian (EAS) ancestries. Results: A total of 474,450 EUR participants and 351,653 EAS participants were included for either forward or reverse MR analysis. In our primary analysis, we found significant evidence of an increased risk of ILD associated with RA among individuals of EUR ancestry (ORMR-cML = 1.08; 95% confidence interval [CI] = 1.03-1.14; p = 0.003) and EAS ancestry (ORMR-cML = 1.37; 95% CI = 1.23-1.54; p < 0.001). Additionally, the reverse MR showed significant evidence of an increased risk of RA associated with ILD among those of EUR ancestry (ORMR-cML = 1.12; 95% CI = 1.05-1.19; p < 0.001). However, only one instrumental variable was selected in the EAS ILD GWAS, and there was no increased risk of RA associated with ILD in those of EAS ancestry (ORMR-cML = 1.02; 95% CI = 0.91-1.14; p = 0.740). Conclusions: Our findings indicate that RA and ILD have a bidirectional causal inference when using the MR analysis of GWAS datasets. The findings are only relevant for genetic predisposition; thus, further research is needed to determine the impact of non-genetic predispositions.

Causal role of 731 immune cells in diabetic nephropathy: a bi-directional two-sample Mendelian randomization study.

The primary cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN), and a growing body of research indicates that immunology plays a part in how DN develops into ESRD. Our objective is to identify causal relationships between various immune invading cells and DN to identify possible targets for immunotherapy. This study used a complete Mendelian randomization (MR) analysis with two samples to identify the underlying mechanism linking immune cell characteristics with DN. Using publicly available genetic data, we investigated the causal link between 731 immune cell profiles and DN risk. Included were four different types of immune systems: morphological parameters (MP), absolute cell (AC), relative cell (RC), and median fluorescence intensities (MFI). The results' robustness, heterogeneity, and horizontal pleiotropy were confirmed through extensive sensitivity analysis. Following FDR (False Discovery Rate correction method) correction, no statistically significant differences were observed; however, six immunophenotypes were shown to be significantly associated with DN risk at the 0.25 level. Only CD28+ CD4- CD8- T cells were identified as the protective immunophenotype (OR = 0.588, 95% CI 0.437-0.792, P = 4.71 × 10-4). Moreover, DN had no discernible impact on immunophenotyping after FDR correction. Surprisingly, three unadjusted phenotypes with low P values were discovered to be positively correlated with the risk of DN: CD20 on IgD- CD27- B cells (OR = 1.263, 95% CI 1.076-1.482, P = 4.22 × 10-3), CD8 on naive CD8 + T cells with Effector Memory (OR = 1.107, 95% CI 1.013-1.209, P = 2.40 × 10-2), and CD8 on Effector Memory CD8 + T cells (OR = 1.126, 95% CI 1.024-1.239, P = 1.46 × 10-2). Our findings provide a genetic basis for the association between immune cells and DN and should inform future clinical research.

Genetic Determinants of Telomere Length and Risk of Aneurysmal Subarachnoid Hemorrhage: A Bidirectional Two-Sample Mendelian Randomization Study

Background Our objective is to investigate the potential causal relationship between telomere length (TL) and aneurysmal subarachnoid hemorrhage (aSAH) and intracranial aneurysms (IAs) by conducting a bidirectional two-sample Mendelian Randomization (MR) study. Methods We utilized publicly available summary data from genome-wide association studies (GWAS) for comprehensive analysis. Telomere length-associated data were sourced from the Epidemiology Unit (IEU) GWAS database (n = 472,174), while data pertaining to intracranial aneurysms were derived from a GWAS meta-analysis conducted by Bakker et al, encompassing aneurysmal subtypes including aSAH (n = 77,074), IAs (n = 79,429), and unruptured intracranial aneurysms (uIA) (n = 74,004), all sampled from European populations. The primary method for MR analysis employed was the Inverse Variance Weighted (IVW) method. Additionally, we conducted various sensitivity analyses to assess the heterogeneity and pleiotropy of study findings. Reverse MR analysis was employed to explore potential reverse causality. Results In the forward MR analysis, the IVW method indicated a negative association between TL and aSAH (OR = 0.636, 95% CI: 0.459–0.883, p = 0.006) as well as IAs (OR = 0.670, 95% CI: 0.499–0.900, p = 0.0079). There was no evidence of heterogeneity or horizontal pleiotropy in the forward MR analysis. Reverse MR analysis did not reveal any causal relationship between aSAH, IAs, uIA and TL. Conclusions In European populations, there exists a causal relationship between longer TL and reduced risks of aSAH and IAs Further research is warranted to elucidate the underlying mechanisms and the potential of TL as an intervention target for lowering the incidence of aSAH and IAs.

Causal relationship between beta-2 microglobulin and B-cell malignancies: genome-wide meta-analysis and a bidirectional two-sample Mendelian randomization study.

Beta-2 microglobulin (β2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of β2M on B-cell malignancy risk, and vice versa, are limited. We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between β2M and B-cell malignancies and the underlying biological processes. The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with β2M. In the UKB, genetically predicted β2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in β2M; 95% confidence interval [CI]: 1.215-2.498; P = 3.00 × 10-3; FDR = 7.50× 10-3) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525-3.380; P = 5.15 × 10-5; FDR =2.58 × 10-4). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and β2M. In FinnGen, β2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; P = 8.28 × 10-4; FDR = 4.14 × 10-3), HL (OR: 1.581; 95% CI: 1.167-2.142; P = 3.13 × 10-3; FDR = 5.22 × 10-3), and FL (OR: 2.113; 95% CI: 1.292-3.455; P = 2.90 × 10-3; FDR = 5.22 × 10-3). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb β2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying β2M, DLBCL, and HL. Our findings suggested that elevated levels of β2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system.

The Causal Relationship between Inflammatory Cytokines and Liver Cirrhosis in European Descent: A Bidirectional Two-Sample Mendelian Randomization Study and the First Conclusions.

Observational studies have highlighted the pivotal role of inflammatory cytokines in cirrhosis progression. However, the existence of a causal link between inflammatory cytokines and cirrhosis remains uncertain. In this study, we conducted a bidirectional Mendelian randomization (MR) analysis at a summarized level to illuminate the potential causal relationship between the two variables. This study utilized genetic variance in cirrhosis and inflammatory cytokines from a genome-wide association study (GWAS) of European descent. The MR-PRESSO outlier test, Cochran's Q test, and MR-Egger regression were applied to assess outliers, heterogeneity, and pleiotropy. The inverse variance weighted method and multiple sensitivity analyses were used to evaluate causalities. Furthermore, the validation set was used for simultaneous data validation. The inflammatory cytokine monocyte chemoattractant protein 3 (MCP-3) was supposedly associated with a greater risk of cirrhosis. And cirrhosis was significantly correlated with increased levels of hepatocyte growth factor (HGF). This study suggests that MCP-3 might be associated with the etiology of cirrhosis, while several inflammatory cytokines could potentially play a role in its downstream development. Additionally, the progression of cirrhosis was associated with elevated levels of HGF, suggesting a possible role for liver repair functions.

Causal effects of plasma metabolites on autoimmune hepatitis (AIH): a bidirectional two-sample mendelian randomization study

Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10− 5,OR: 0.62, 95% CI 0.49–0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67–1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.

Evidence for a Causal Relationship between Heart Failure and Cerebral Infarction: A Bidirectional Two-Sample Mendelian Randomization Study

Evidence for a Causal Relationship between Heart Failure and Cerebral Infarction: A Bidirectional Two-Sample Mendelian Randomization Study

Causal relationship between gut microbiota and insulin-like growth factor 1: a bidirectional two-sample Mendelian randomization study.

The causal relationship between gut microbiota and insulin-like growth factor 1 (IGF-1) remains unclear. The purpose of this study was to explore the causal relationship between gut microbiota and IGF-1 in men and women. Single-nucleotide polymorphisms (SNPs) related to gut microbiota were derived from pooled statistics from large genome-wide association studies (GWASs) published by the MiBioGen consortium. Pooled data for IGF-1 were obtained from a large published GWAS. We conducted Mendelian randomization (MR) analysis, primarily using the inverse variance weighted (IVW) method. Additionally, we performed sensitivity analyses to enhance the robustness of our results, focusing on assessing heterogeneity and pleiotropy. In forward MR analysis, 11 bacterial taxa were found to have a causal effect on IGF-1 in men; 14 bacterial taxa were found to have a causal effect on IGF-1 in women (IVW, all P < 0.05). After false discovery rate (FDR) correction, all bacterial traits failed to pass the FDR correction. In reverse MR analysis, IGF-1 had a causal effect on nine bacterial taxa in men and two bacterial taxa in women respectively (IVW, all P < 0.05). After FDR correction, the causal effect of IGF-1 on order Actinomycetales (PFDR = 0.049) remains in men. The robustness of the IVW results was further confirmed after heterogeneity and pleiotropy analysis. Our study demonstrates a bidirectional causal link between the gut microbiota and IGF-1, in both men and women.

Causal associations between frailty and low back pain: a bidirectional two-sample mendelian randomization study

BackgroundPrevious observational studies have revealed a potentially robust bidirectional relationship between frailty and low back pain (LBP). However, the precise causal relationship remains unclear.MethodsTo examine the potential causal association between frailty and LBP, we conducted bidirectional two-sample Mendelian randomization analysis (MR) study. Genetic data on frailty index (FI) and LBP were acquired from publicly available genome-wide association studies (GWAS). Various MR methodologies were utilized, such as inverse variance weighting (IVW), weighted median, and MR-Egger, to evaluate causality. Additionally, sensitivity analyses were conducted to evaluate the robustness of the findings.ResultsGenetically predicted higher FI (IVW, odds ratio [OR] = 1.66, 95% CI 1.17–2.36, p = 4.92E-03) was associated with a higher risk of LBP. As for the reverse direction, genetic liability to LBP showed consistent associations with a higher FI (IVW, OR = 1.13, 95% CI 1.07–1.19, p = 2.67E-05). The outcomes from various MR techniques and sensitivity analyses indicate the robustness of our findings.ConclusionOur research findings provide additional evidence bolstering the bidirectional causal relationship between frailty and LBP.

Causal association between mitochondrial function and psychiatric disorders: Insights from a bidirectional two-sample Mendelian randomization study

BackgroundPrevious observational studies have suggested that there appears to be a close association between mitochondrial function and psychiatric disorders, but whether a causal role exists remains unclear. MethodsWe extracted genetic instruments for 67 mitochondrial-related proteins and 10 psychiatric disorders from publicly available genome-wide association studies, and employed five distinct MR methods and false discovery rate correction to detect causal associations between them. Additionally, we conducted a series of sensitivity tests and additional model analysis to ensure the robustness of the results. For potential causal associations, we further performed reverse MR analyses to assess the impact of reverse causality. ResultsWe identified a total of 2 significant causal associations and 24 suggestive causal associations. Specifically, Phenylalanine-tRNA ligase was found to increase the risk of Alzheimer's disease, while Mitochondrial glutamate carrier 2 decreased the risk of autism spectrum disorder. Furthermore, there was no evidence of significant pleiotropy, heterogeneity, or reverse causality. LimitationsThis study was limited to individuals of European ancestry, and the conclusions drawn are merely revelatory. ConclusionThis study provides novel insights into the relationship between mitochondria and psychiatric disorders, as well as the pathogenesis and treatment strategies for psychiatric disorders.

Association between iron status, preeclampsia and gestational hypertension: A bidirectional two-sample Mendelian randomization study

BackgroundSeveral recent observational studies have reported that iron overload during pregnancy is associated with preeclampsia (PE) and gestational hypertension (GH). However, the causal association between iron status, PE, and GH is still not clear. MethodsWe performed a two-sample Mendelian randomization (MR) study using the genome-wide association study (GWAS) summary statistics of iron status, included serum iron, ferritin, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) from the largest available GWAS meta-analysis, and the summary statistics of PE and GH were obtained from the FinnGen consortium. Fixed-effect inverse variance weighted (IVW), random-effect IVW, maximum likelihood (ML), MR-Egger regression, weighted median, and MR-PRESSO methods were used. ResultsA total of 21, 58, 28, and 22 SNPs were used as IVs for serum iron, ferritin, TIBC, and TSAT, respectively. The F-statistics of IVs ranged from 95.23 to 421.36. The results of the fixed effects IVW method suggested that for per SD unit increase in serum iron, the risk of PE increases by 24 % (OR = 1.24, 95 % CI: 1.03–1.50, P = 0.02). No significant heterogeneity or horizontal pleiotropy was found. The association between ferritin, TIBC, TSAT and PE were statistically insignificant (P>0.05). Furthermore, the results of each MR methods do not support a causal association between iron status and GH, nor a reverse causal association between PE and GH and iron status. ConclusionThis two-sample MR study provides evidence supporting a causal association between serum iron level and PE.