MR-Egger Regression Research Articles

A mendelian randomisation study of the causal effect of exercise intensity on the development of type 2 diabetes.

This study examines the causal effects of varying exercise intensities on type 2 diabetes mellitus (T2D) through Mendelian randomization (MR) analysis, using genetic variants as instrumental variables. A two-sample MR analysis was performed, employing Inverse Variance Weighted (IVW) as the primary method, supported by weighted median, MR-Egger regression, MR-PRESSO, and MR robustness-adjusted contour scores. Data were obtained from the International Exercise Genetics Database (IEGD) and the Global Diabetes Research Consortium (GRC), encompassing over 150,000 individuals for exercise intensity and around 200,000 T2D patients and controls. SNPs linked to exercise intensity were selected based on genome-wide significance (P < 5 × 10^-8) and linkage disequilibrium criteria (distance >10,000kb, r^2 < 0.001). The IVW analysis suggested that high-intensity exercise might reduce T2D risk, but the association was not statistically significant (OR = 0.667, 95% CI = 0.104-4.255, P = 0.667). The wide confidence interval indicates uncertainty in the effect estimate. Low-intensity exercise showed no significant effect on T2D risk (OR ∼ 1.0). Sensitivity analyses, including weighted median and MR-Egger regression, confirmed no significant association between high-intensity exercise and T2D risk. The MR-PRESSO analysis found no significant outliers, and the global test for pleiotropy was non-significant (P = 0.455). Cochran's Q test for heterogeneity in the IVW analysis was non-significant (Q = 12.45, P = 0.234), indicating consistency among SNP-derived estimates. High-intensity exercise potentially reduces T2D risk, but the association is not statistically significant. Further research is needed to understand the complex relationship between exercise intensity and T2D.

Does autoimmune diseases increase the risk of frailty? A Mendelian randomization study.

The causality of autoimmune diseases with frailty has not been firmly established. We conducted this Mendelian randomization (MR) study to unveil the causal associations between autoimmune diseases with frailty. A MR analyses were performed to explore the relationships between autoimmune disease and frailty, using summary genome-wide association statistics. Through a comprehensive and meticulous screening process, we incorporated 46, 7, 12, 20, 5, and 53 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for hypothyroidism, hyperthyroidism, rheumatoid arthritis (RA), type 1 diabetes (T1D), multiple sclerosis (MS), and overall autoimmune disease, respectively. Our analysis revealed that hypothyroidism (OR = 1.023, 95% CI: 1.008-1.038, p = 0.0015), hyperthyroidism (OR = 1.024, 95% CI: 1.004-1.045, p = 0.0163), RA (OR = 1.031, 95% CI: 1.011-1.052, p = 0.0017), T1D (OR = 1.011, 95% CI: 1.004-1.017, p = 0.0012), and overall autoimmune disease (OR = 1.044, 95% CI: 1.028-1.061, p = 5.32*10^-8) exhibited a positive causal effect on frailty. Conversely, there may be a negative causal association between MS (OR = 0.984, 95% CI: 0.977-0.992, p = 4.87*10^-5) and frailty. Cochran's Q test indicated heterogeneity among IVs derived from hypothyroidism, hyperthyroidism, T1D, and overall autoimmune diseases. The MR-Egger regression analyzes revealed an absence of horizontal pleiotropy in any of the conducted analyses. This study elucidates that hypothyroidism, hyperthyroidism, RA, T1D, and overall autoimmune disease were linked to an elevated risk of frailty. Conversely, MS appears to be associated with a potential decrease in the risk of frailty.

Mendelian randomization study of childhood asthma and chronic obstructive pulmonary disease in European and East Asian population

ObjectiveThe present study aimed to explore the potential causal relationship between childhood asthma and chronic obstructive pulmonary disease (COPD) in European and East Asian populations with Mendelian randomization (MR) analysis. MethodsBased on summary data from genome-wide association studies, single nucleotide polymorphisms (SNPs) associated with childhood asthma were used as instrumental variables. The MR analysis employed the inverse variance weighting, MR-Egger regression and weighted median method to estimate the causal effect between childhood asthma and COPD in European and East Asian populations. Cochran's Q test, MR-PRESSO method and MR-Egger intercept were used to detect heterogeneity, outliers and horizontal pleiotropy, respectively. Leave-one-out analysis applied to assess the effect of removing individual SNP on the estimate of causal association. ResultsThe MR analysis showed no genetic causal relationship between childhood asthma and COPD. The results of Cochran's Q test, MR-PRESSO and MR-Egger regression indicated the absence of heterogeneity, outliers and horizontal pleiotropy, respectively. Leave-one-out analysis showed no significant difference in the statistical results after exclusion of single SNPs. ConclusionsThe MR analysis revealed that there is no causal relationship between childhood asthma and COPD at the genetic level in both European and East Asian populations. Additionally, due to the presence of shared confounding factors and pathogenic genes, further research is needed to comprehensively assess the relationship between childhood asthma and COPD.

Vitamin D and Gestational Diabetes Mellitus in the IEU OpenGWAS Project: A Two-Sample Bidirectional Mendelian Randomization Study.

Gestational diabetes mellitus (GDM) is one of the most prevalent pregnancy problems, and there is still debate over the relationship between vitamin D and GDM. Our objective is to investigate the correlation between vitamin D and GDM by employing Mendelian randomization (MR) with summary data obtained from genome-wide association studies (GWAS). Data on exposures and outcomes, namely vitamin D, vitamin D insufficiency, and GDM, were acquired from the IEU OpenGWAS Project. Bidirectional MR analysis was performed utilizing the inverse variance weighted (IVW) method as the principal analytical approach. The complementary approaches employed in this study encompassed weighted median, simple mode, weighted mode, and MR-Egger regression. A series of sensitivity analysis were conducted in order to assess the reliability of the obtained results. The data were acquired from the IEU OpenGWAS Project. Following the application of the three assumptions of MR, 13 single nucleotide polymorphisms (SNPs) were included in the MR analysis for vitamin D levels and vitamin D deficiency on GDM, and 10 and 26 SNPs were included for GDM on vitamin D levels and deficiency, respectively. The findings from the IVW analysis revealed a significant positive correlation between vitamin D levels and GDM (OR = 1.057, 95% CI: 1.011-1.104, p = 0.015). Conversely, a negative correlation was seen between vitamin D deficiency and GDM (OR = 0.979, 95% CI: 0.959-0.999, p = 0.039). The results of the reverse MR study revealed no evidence of reverse causation between GDM and vitamin D. The findings from multiple MR approaches were in line with the direction of IVW analysis. Sensitivity analysis revealed no evidence of heterogeneity, pleiotropy, or outliers, suggesting the robustness of the results. There exists a causal association between vitamin D and GDM, whereby vitamin D levels serve as a risk factor for GDM.

Causal association between blood leukocyte counts and vascular dementia: a two-sample bidirectional Mendelian randomization study

While previous observational studies have suggested a link between leukocyte counts and vascular dementia (VD), the causal relationship between leukocyte counts and various subtypes of VD remains elusive. This study aimed to investigate the causal relationship between five types of leukocyte counts and VD, with the goal of improving prevention and treatment strategies. In this study, leukocyte counts were used as the exposure variable, with genome-wide association study (GWAS) data sourced from both the UK Biobank and the Blood Cell Consortium. Additionally, GWAS data for five subtypes of vascular dementia were obtained from the FinnGen database. We conducted rigorous statistical analysis and visualization using Mendelian randomization (MR) to elucidate the potential causal relationship between leukocyte counts and vascular dementia. This study, utilizing MR analysis with data from the UK Biobank and Blood Cell Consortium, identified significant causal associations between increased lymphocyte counts and VD. Specifically, lymphocyte counts were found to be causally related to multiple and mixed VD subtypes. Sensitivity analyses, including MR-Egger regression and MR-PRESSO tests, confirmed the robustness of these findings, with no evidence of reverse causality or significant horizontal pleiotropy detected. The results underscore a potential inflammatory or immunological mechanism in the pathogenesis of VD, highlighting lymphocytes as a key component in their etiology. This investigation establishes a robust association between elevated lymphocyte and leukocyte counts and an increased risk of VD, emphasizing the roles of inflammation, immune activation, and hematological factors in disease pathogenesis.

Exploring the Missing link between vitamin D and autism spectrum disorder: Scientific evidence and new perspectives

AimThis study aims to address the key question of the causal relationship between serum levels of 25-hydroxyvitamin D (vitamin D) and autism spectrum disorders (ASD). MethodsPublicly available Genome-Wide Association Study (GWAS) datasets were used to conduct the bidirectional Two-sample MR analyses using methods including inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, MR-PRESSO test, Steiger filtering, and weighted mode, followed by BWMR for validation. ResultsThe MR analysis indicated that there was no causal relationship between Vitamin D as the exposure and ASD as the outcome in the positive direction of the MR analysis (IVW: OR = 0.984, 95 % CI: 0.821–1.18, P = 0.866). The subsequent BWMR validation stage yielded consistent results (OR = 0.984, 95 % CI 0.829–1.20, P = 0.994). Notably, in the reverse MR analysis with ASD as the exposure and Vitamin D as the outcome, the results suggested that the occurrence of ASD could lead to decreased Vitamin D levels (IVW: OR = 0.976, 95 % CI: 0.961–0.990, P = 0.000855), with BWMR findings in the validation stage confirming the discovery phase (OR = 0.975, 95 % CI: 0.958–0.991, P = 0.00297). For the positive MR analysis, no pleiotropy was detected in the instrumental variables. Similarly, no pleiotropy or heterogeneity was detected in the instrumental variables for the reverse MR analysis. Sensitivity analysis using the leave-one-out approach for both positive and reverse instrumental variables suggested that the MR analysis results were robust. ConclusionThrough the discovery and validation analysis process, we can confidently assert that there is no causative link between Vitamin D and ASD, and that supplementing Vitamin D is not expected to provide effective improvement for patients with ASD. Our study significantly advances a new perspective in ASD research and has a positive impact on medication guidance for patients with ASD.

Investigation of the anti-skin aging effects of taurine through mendelian randomization analysis of its relationship with immune cells.

Aging skin, exacerbated by external factors like UV radiation and pollutants, is a major cosmetic concern. Taurine, renowned for its antioxidant and anti-inflammatory properties, may combat skin aging. We performed mendelian randomization (MR) analysis to investigate the causal link between taurine and immune cells linked to skin aging. To investigate the association between taurine and immune cells using mendelian randomization, to thereby explore the mechanism through which taurine exerts anti-aging effects on the skin via immune modulation. A MR approach was employed using taurine-level data from the Ieu Open GWAS Project and immunocyte traits from a large European cohort. MR-Egger regression, weighted median estimation, and inverse variance weighting all provided statistical insights into causality. Sensitivity analyses assessed the heterogeneity and pleiotropy among the genetic instruments used. MR analysis identified a causal relationship between taurine levels and 10 immunocyte phenotypes, with taurine found to be negatively and positively associated with three and seven phenotypes, respectively. Sensitivity analysis revealed no significant heterogeneity or pleiotropy, suggesting reliable MR findings. This study provides insights into the immunological pathways by which taurine contributes to skin anti-aging effects, suggesting that increasing taurine levels could offer a novel strategy for anti-aging skincare.

Genetically predicted circulating concentrations of micronutrients and risk of autoimmune thyroiditis: a Mendelian randomized study.

Micronutrients play pivotal roles in modulating various aspects of the immune response. However, the existing literature on the association between micronutrients and autoimmune thyroiditis (AIT) remains limited and contentious. To address this gap, we conducted Mendelian randomization (MR) to investigate potential links between genetically predicted concentrations of six micronutrients (Copper (Cu), Iron (Ir), Calcium (Ca), Vitamin D (VD), Vitamin C (VC), Zinc (Zn)) and the risk of AIT. Utilizing summary statistics from genome-wide association studies (GWAS) in individuals of European descent, we employed MR methodologies to elucidate the interplay between micronutrients and AIT. Three distinct MR techniques were employed: Inverse Variance Weighted (IVW), MR-Egger regression, and Weighted Median Estimator (WME). Additionally, we evaluated outcome heterogeneity using Cochran's Q statistic and assessed pleiotropy using the MR-Egger intercept. IVW analysis revealed no substantial evidence supporting a significant impact of genetically predicted micronutrient concentrations on AIT risk (Cu: OR = 0.918, P = 0.875; Ir: OR = 0.653, P = 0.264; Ca: OR = 0.964, P = 0.906; VD: OR = 0.717, P = 0.378; VC: OR = 0.986, P = 0.875; Zn: OR = 0.789, P = 0.539). Cochran's Q test for IVW indicated no notable heterogeneity. Moreover, the MR-Egger intercept method suggested the presence of horizontal pleiotropy between serum VC levels and AIT (MR-Egger intercept = -0.037, p = 0.026), while no such pleiotropy was observed for other micronutrients. Our MR analysis does not support a causal relationship between genetically predicted concentrations of six micronutrients (Cu, Ir, Ca, VD, VC, and Zn) and the risk of AIT.

COVID-19, vaccination and migraine: Causal association or epiphenomenon?

Diverse studies have revealed discrepant evidence concerning the causal association between Corona Virus Disease 2019 (COVID-19) and COVID-19 vaccination in relation to migraines. Investigating the correlation between the former two factors and migraines can facilitate policymakers in the precise formulation of comprehensive post-pandemic interventions while urging the populace to adopt a judicious perspective on COVID-19 vaccination. We undertook a Mendelian randomization (MR) study. The primary assessment of the causal relationship between the three different COVID-19 exposures and migraine was conducted using the standard inverse variance weighted (IVW) approach. In the supplementary analysis, we also employed two methodologies: the weighted median estimator (WME) and the MR-Egger regression. Ultimately, the reliability and stability of the outcomes were assessed via Cochran's Q test, the leave-one-out method, the MR-Egger intercept test, and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. The results indicate an absence of correlation between genetically predicted COVID-19 (①Very severe respiratory confirmed COVID-19: odds ratio [OR], 1.0000881; 95%CI, 0.999748-1.000428; p = 0.6118; ②Hospitalized COVID-19: OR, 1.000024; 95%CI, 0.9994893-1.000559; p = 0.931;③SARS-CoV-2 infection: OR, 1.000358; 95%CI, 0.999023-1.001695; p = 0.5993) and the risk of migraine. Furthermore, the MR-Egger regression and WME also yielded no evidence of COVID-19 elevating the risk of migraine occurrence. Sensitivity analysis affirmed the robustness and consistency of all outcomes. The results of this study do not offer genetic evidence to substantiate a causal relationship between COVID-19 and migraines. Thus, the deduction drawn from COVID-19 genetic data is that COVID-19 vaccination is unlikely to exert an impact on the occurrence of migraines, though this conclusion warrants further investigation.

Exploration of causal relationship between shoulder impingement syndrome and rotator cuff injury: a bidirectional mendelian randomization

BackgroupThe pathogenesis of shoulder impingement syndrome (SIS) is still unclear, and its questionable causal relationship with rotator cuff (RC) injury has led to confusion in treatment. The purpose of this study was to explore the bidirectional causal relationship between SIS and RC injury.MethodsSIS and RC injury datasets downloaded from the IEU Open GWAS project and GWAS catalog databases. Inverse variance weighted (IVW), MR Egger, Weighted median, and Weighted mode were used in this Mendelian randomization (MR) analysis. Cochran’s Q test, leave-one-out, and funnel plot method were used to evaluate heterogeneity between single nucleotide polymorphisms (SNPs). MR-Egger regression was used to test the horizontal pleiotropy of this study.ResultsThe IVW method (OR = 1.189, P = 0.0059) suggest the putative causal effect of RC injury on SIS. The results of MR Egger method (OR = 1.236, P = 0.2013), weighted median method (OR = 1.097, P = 0.2428) and weighted mode method (OR = 1.013, P = 0.930) showed no statistically significant (OR = 1.069071, P = 0.6173). Heterogeneity test and horizontal pleiotropy analysis suggested that there was no significant heterogeneity and horizontal pleiotropy in the results of this MR analysis. The reverse MR analysis showed heterogeneity, and the conclusion needs to be further explored.ConclusionsThe results of MR analysis support that RC injury may be causally associated with SIS.

Genetic Susceptibility of Thrombin Measurement Levels and the Risk of Colon Adenocarcinoma: A Mendelian Randomization Study.

Aims/Background: This investigation sought to establish a possible correlation between thrombin measurement levels and the risk of developing colon adenocarcinoma (COAD). Methods: Thrombin measurement levels were sourced from a study by Pietzner M (2020, PMID: 33328453) and integrated into the IEU database. Data on COAD were obtained from the FinnGen database (2021, C3_COLON_ADENO). Various analytical methods were used to assess the relationship, including inverse variance weighting (IVW), mendelian randomization-Egger (MR-Egger) regression, as well as weighted median and mode techniques. Sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, mendelian randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), along with leave-one-out analysis, to ensure the robustness of the results. Results: The IVW analysis indicated a significant inverse association between elevated thrombin levels and the risk of COAD (odds ratio (OR) = 0.76, 95% CI = 0.66-0.88, p = 0.0003). These findings were supported by the weighted median analysis (OR = 0.78, 95% CI = 0.68-0.90, p = 0.0006) and the weighted mode analysis (OR = 0.78, 95% CI = 0.68-0.88, p = 0.0017). Conclusion: This research identified an inverse causal relationship between thrombin measurement levels and the incidence of COAD, suggesting that higher thrombin levels are associated with a reduced risk of developing COAD.

Causal link between metabolic related factors and osteoarthritis: a Mendelian randomization investigation.

Metabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification. Two-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity. The UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified. The MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

Genetically Determined Circulating Saturated and Unsaturated Fatty Acids and the Occurrence and Exacerbation of Chronic Obstructive Pulmonary Disease-A Two-Sample Mendelian Randomization Study.

Research on dietary fatty acids (FAs) and lung health has reported skeptical findings. This study aims to examine the causal relationship between circulating FAs and Chronic Obstructive Pulmonary Disease (COPD) onset and exacerbation, using a two-sample Mendelian Randomization (MR) analysis. Strong and independent genetic variants of FAs were obtained from the UK Biobank of European ancestry. The exposure traits included saturated FA (SFA), poly- and mono-unsaturated FA (PUFA and MUFA), omega-3 and omega-6 PUFA, docosahexaenoic acid (DHA), and linoleic acid (LA), all expressed as total FA (TFA) percentages. Summary statistics for COPD outcomes were obtained from the FinnGen consortium including COPD, COPD hospitalization, COPD/asthma-related infections, COPD-related respiratory insufficiency, and COPD/asthma/interstitial lung disease (ILD)-related pneumonia. The inverse-variance weighted (IVW) was the primary MR approach. MR-Egger regression and MR-PRESSO were utilized to evaluate heterogeneity and pleiotropy. MR-PRESSO tests suggested no obvious horizontal pleiotropy. MR results by the IVW approach indicated that the genetically high SFA/TFA levels were associated with an increased risk of COPD/asthma/ILD-related pneumonia (OR: 1.275, 95%CI: 1.103-1.474, p for FDR = 0.002). No significant relationship was observed between other types of FAs and COPD outcomes. Our MR analysis suggests that there is weak evidence that the genetically predicted high SFA/TFA was associated with an increased risk of pneumonia.

Genetic associations between ULK3 and epilepsy: a two-sample Mendelian randomization study.

Observational studies have suggested that a multitude of pathological processes and biomolecules are involved in the initiation and development of epilepsy, and ULK3 is linked to the nervous system. However, it remains uncertain whether this association between ULK3 and epilepsy is causal and the direction of any causal relationship. This study employs a two-sample Mendelian randomization (MR) method to investigate the relationship between ULK3 and the risk of epilepsy. We analyzed genome-wide association study (GWAS) summary statistics for ULK3 (sample size = 3,301), focal epilepsy (sample size = 39,348), and generalized epilepsy (sample size = 33,446). Bidirectional MR analyses were conducted to explore these relationships. We selected a set of single nucleotide polymorphisms (SNPs) with an association threshold of less than 1 × 10-5 as instrumental variables for further analysis. Various MR methods, including Inverse Variance Weighted, Weighted Median, MR-Egger Regression, Simple Model, Weighted Model, and Robust Adjustment Profile Score were used. Sensitivity analyses were performed to ensure the robustness of the results. Our MR analyses revealed a causal relationship where an increased level of ULK3 was associated with a decreased risk of focal epilepsy (odds ratio = 0.92, 95% confidence interval: 0.86-1.00, p = 0.041). No significant heterogeneity (Q = 7.85, p = 0.165) or horizontal pleiotropy (Egger regression intercept = 0.0191, p = 0.415) was detected. However, in the reverse analysis, we found no significant causal effect of focal epilepsy on ULK3 (p > 0.05). Furthermore, no significant causation was identified between ULK3 and generalized epilepsy (p > 0.05). This study suggests a causal relationship between ULK3 and the risk of focal epilepsy from a genetic perspective. Nevertheless, further investigation is needed to understand the role of ULK3 in epilepsy fully.

Gut microbiota, allergic rhinitis, vasomotor rhinitis, Mendelian randomization, causal association

ObjectiveContinuous research on the structure and function of intestinal microecology has confirmed the association between gut microbiota and the occurrence, development, and outcome of allergic diseases. Here, we explored the genetic causality between gut microbiota and rhinitis. MethodsWe conducted a two-sample Mendelian Randomization (MR) study to investigate the genetic causal relationship between gut microbiota and allergic rhinitis and vasomotor rhinitis. Genetic variations in the human gut microbiota were obtained from the summary statistics of the MiBioGen study. Genome-wide summary statistics of rhinitis were obtained from the FinnGen consortium. The causal effect between gut microbiota and rhinitis was assessed using the inverse variance weighted, MR-Egger regression, and weighted median methods. In addition, sensitivity analyses were conducted using different methods, including maximum likelihood, simple mode, and weighted model methods. ResultsThe IVW approach revealed a causal association of the genus Ruminococcus gauvreauii group with an increased risk of allergic rhinitis (IVW Odds Ratio [OR = 1.26] [1.04, 1.53], p-value = 0.01645). In addition, the genus Fusicatenibacter (IVW OR = 1.20 [1.02, 1.41], p-value = 0.02868) was causally associated with an increased risk of vasomotor rhinitis. ConclusionGut microbiota belonging to different genera exert different effects on allergic rhinitis and vasomotor rhinitis, including reducing the risk of rhinitis, and increasing the risk of rhinitis. New insights into the mechanisms of underlying gut microbiota-associated rhinitis are provided. Level of evidenceLevel 5.

Causal association between cystatin C and diabetic retinopathy: A two-sample Mendelian randomization study.

To explore the causal relationship between cystatin C levels and different stages of diabetic retinopathy through Mendelian randomization (MR). The MRC Integrative Epidemiology Unit provided the Genome-wide association studies (GWAS) data related to cystatin C (exposure). GWAS data for outcomes [DR, proliferative diabetic retinopathy (PDR), severe non-proliferative background diabetic retinopathy (SNPBDR)] were sourced from the FinnGen. Adopted Inverse Variance Weighting (IVW), MR-Egger regression MR-PRESSO, Weighted Median, Constrained Maximum Likelihood and Model Averaging (cML-MA), Weighted model, Radial MR, and MR-Lasso to estimate the causal relationship between cystatin C and diabetic retinopathy. We conducted multivariable MR analysis to evaluate the independent causal effects of cystatin C levels on diabetic retinopathy. Based on the IVW method, we observed a causal relationship between cystatin C and diabetic retinopathy [odds ratio (OR)random effect = 1.137, 95% confidence interval (CI): 1.035-1.250]/PDR (ORrandom effect = 1.123, 95%CI: 1.004-1.255)/SNPBDR (ORfixed effect = 2.002, 95%CI: 1.343-2.986). Consistent findings were obtained through the cML-MA method. Cochran's Q test suggested the presence of heterogeneity between the cystatin C level and instrumental variables in relation to diabetic retinopathy and proliferative diabetic retinopathy, respectively. After adjusting for outliers using MR-PRESSO and Radial MR, it was observed that the statistical significance of the association between cystatin C level and diabetic retinopathy persists. Reverse MR analysis indicated that genetically related SNPBDR may influence the cystatin C level. In multivariable MR analysis, there were indications suggesting a causal relationship of cystatin C with the risk of DR/PDR/SNPBDR adjusting for confounders. This study utilizes Mendelian randomization analyses to establish a causal relationship between cystatin C and diabetic retinopathy, and reveals the impact of cystatin C on the risk of diabetic retinopathy, thus providing new evidence for clinical intervention of diabetic retinopathy.

Exploring the relationship between gut microbiota and breast cancer risk in European and East Asian populations using Mendelian randomization

BackgroundSeveral studies have explored the potential link between gut microbiota and breast cancer; nevertheless, the causal relationship between gut microbiota and breast cancer remains unclear.MethodsWe utilized summary statistics from genome-wide association studies (GWAS) of the gut microbiome from the MiBioGen project with summary data from GWAS on breast cancer from the FinnGen consortium and the IEU database, with the IEU data sourced from the Biobank Japan. Preliminary statistical analyses were conducted using inverse variance weighting (IVW), supplemented by various sensitivity analysis methods, including MR-Egger regression, weighted median, weighted mode, simple median, and simple mode, to ensure the robustness of our findings. Heterogeneity and pleiotropy were assessed to avoid misleading conclusions caused by unconsidered confounders or non-specific effects of genetic variants, ensuring that the results reflect a genuine causal relationship.ResultsIn European populations, four types of gut microbiota were associated with breast cancer. The genus Erysipelatoclostridium was positively associated with the risk of breast cancer, with an odds ratio (OR) of 1.21 (95% confidence interval [CI] 1.083–1.358), false discovery rate (FDR) = 0.0039. The class Coriobacteriia, order Coriobacteriales, and family Coriobacteriaceae, which belong to the same phylogenetic system, showed a consistent inversely association with breast cancer risk, with an OR of 0.757 (95% CI 0.616–0.930), FDR = 0.0281. In East Asian populations, three types of gut microbiota were related to breast cancer. The Eubacterium ruminantium group was positively associated with breast cancer risk, with an OR of 1.259 (95% CI 1.056–1.499), FDR = 0.0497. The families Porphyromonadaceae and Ruminococcaceae were inversely associated with breast cancer risk, with ORs of 0.304 (95% CI 0.155–0.596), FDR = 0.0005, and 0.674 (95% CI 0.508–0.895), FDR = 0.03173, respectively. However, these two taxa had limited instrumental variables, restricting the statistical power and potentially affecting the interpretation of the results.ConclusionThis MR analysis demonstrated a probable causal link between specific gut microbiota and breast cancer. This study, through Mendelian randomization analysis comparing European and East Asian populations, reveals that gut microbiota may influence breast cancer risk differently across populations, providing potential directions for developing targeted prevention and treatment methods.

Elevated Blood Pressure: A Genetically Determined Risk Factor for Cerebral Artery Dissection.

We aim to investigate the potential causal link between blood pressure (BP) levels and cerebral artery dissection (CAD) risk by employing a 2-sample Mendelian randomization (TSMR) framework. Utilizing large-scale genome-wide association studies-retrieved data, we employed various Mendelian randomization (MR) techniques, including inverse variance weighted (IVW), MR-Egger regression, weighted median, and weighted mode, to ascertain BP's causal impact on CAD. The MR-Egger intercept was calculated to assess pleiotropy presence, determining heterogeneity by Cochran's Q statistic. The findings highlighted a significant association between elevated systolic BP (SBP; IVW: OR = 3.09, 95% CI: 1.11-8.61, P = 0.031) and increased diastolic BP (DBP; IVW: OR = 2.17, 95% CI: 1.14-6.21, P = 0.023) with CAD risk. Sensitivity analyses reinforced the robustness and reliability of these results. The results from this TSMR study suggest a causal link between high SBP and DBP and the increased likelihood of CAD, which provides genetic evidence for a reduced risk of CAD under BP control.

Association Between COVID-19 and Osteoporosis: A Bidirectional Mendelian Randomization Study

Objective: The prevalence and severity of covid-19 infection were higher in patients with osteoporosis than in healthy controls, and the mean BMD was lower in patients with COVID-19 than in healthy controls, and low vitamin D levels were associated with the development of osteoporosis and the severity of COVID-19. The objective of this study is to understand whether there was indeed a bidirectional causal relationship between osteoporosis and COVID-19. Methods: Analysis of the causal relationship between the two through a two-way Mendelian pathway. Finding disease-related Single nucleotide Polymorphism as working variables through the Genome-wide association study database. The primary analysis for the Mendelian randomization (MR) study was the inverse variance weighting (IVW) method. The pleiotropy was estimated through the intercept from MR-Egger regression, and heterogeneity was assessed through Cochran’s Q test in IVW approach. Results: In the forward MR analysis, neither exposure to COVID-19 infection, hospitalization or severe infection was significantly associated with osteoporosis or drug-induced osteoporosis outcome (P&gt;0.05); in the reverse MR analysis, exposures to osteoporosis was not significantly associated with COVID-19 outcomes (infection, hospitalization, severe case) (P&gt;0.05). Conclusion: There was no significant relationship between COVID-19 patients and osteoporosis or drug-induced osteoporosis by genetic prediction.

Causal Effects of Asthma on Upper Airway Diseases and Allergic Diseases: A Two-Sample Mendelian Randomization

Introduction: Asthma is associated with upper airway diseases and allergic diseases; however, the causal effects need to be investigated further. Thus, we performed this two-sample Mendelian randomization (MR) analysis to explore and measure the causal effects of asthma on allergic rhinitis (AR), vasomotor rhinitis (VMR), allergic conjunctivitis (AC), atopic dermatitis (AD), and allergic urticaria (AU). Methods: The data for asthma, AR, VMR, AC, AD, and AU were obtained from large-scale genome-wide association studies summarized recently. We defined single-nucleotide polymorphisms satisfying the MR assumptions as instrumental variables. Inverse-variance weighted (IVW) approach under random-effects was applied as the dominant method for causal estimation. The weighted median approach, MR-Egger regression analysis, MR pleiotropy residual sum and outlier test, and leave-one-out sensitivity analysis were performed as sensitivity analysis. Horizontal pleiotropy was measured using MR-Egger regression analysis. Significant causal effects were attempted for replication and meta-analysis. Results: We revealed that asthma had causal effects on AR (IVW, odds ratio [OR] = 1.93; 95% confidence interval [CI], 1.74−2.14; p < 0.001), VMR (IVW, OR = 1.40; 95% CI, 1.15−1.71; p < 0.001), AC (IVW, OR = 1.65; 95% CI, 1.49−1.82; p < 0.001), and AD (IVW, OR = 2.13; 95% CI, 1.82−2.49; p < 0.001). No causal effect of asthma on AU was observed. Sensitivity analysis further assured the robustness of these results. The evaluation of the replication stage and meta-analysis further confirmed the causal effect of asthma on AR (IVW OR = 1.81, 95% CI 1.62–2.02, p < 0.001), AC (IVW OR = 1.44, 95% CI 1.11–1.87, p < 0.001), and AD (IVW OR = 1.85, 95% CI 1.42–2.41, p < 0.001). Conclusions: We revealed and quantified the causal effects of asthma on AR, VMR, AC, and AD. These findings can provide powerful causal evidence of asthma on upper airway diseases and allergic diseases, suggesting that the treatment of asthma should be a preventive and therapeutic strategy for AR, VMR, AC, and AD.