MR Pleiotropy Residual Sum And Outlier Research Articles

Causal effects of retinol and vitamin D on tongue cancer risk: a mendelian randomization study

BackgroundPrevious studies have indicated that retinol and vitamin D may be associated with the oncogenesis of tongue cancer. Therefore, we aimed to assess the causal relationships of retinol and vitamin D with the risk of tongue cancer using the two-sample Mendelian randomization (MR) method.MethodsSingle nucleotide polymorphisms (SNPs) related to retinol, vitamin D and tongue cancer were obtained from the up-to-date genome-wide association study (GWAS) catalogue, which was screened for instrumental variables (IVs). We performed two-sample MR analyses and used inverse-variance weighted (IVW) as the primary method. Additionally, we used the MR-pleiotropy residual sum and outlier (MR-PRESSO) method, MR-Egger intercept analysis, Cochran’s Q test and leave-one-out analysis to evaluate the sensitivity of MR.ResultsThe IVW method revealed that retinol was not significantly correlated with the risk of tongue cancer (OR = 0.8602; 95% CI = 0.4453–1.6617; P = 0.654). However, the causal relationship between vitamin D and the risk of tongue cancer was significant according to IVW (OR = 0.4003; 95% CI = 0.1868–0.8577; P = 0.019). The sensitivity analysis did not detect any significant horizontal pleiotropy or heterogeneity.ConclusionsGiven the limitations of this study, our MR study suggests that retinol is unlikely to influence the risk of tongue cancer, but vitamin D may decrease the risk of tongue cancer.

The association between type 1 diabetes mellitus and the risk of immunoglobulin A nephropathy: a Mendelian randomization study.

To investigate the potential causal relationship between type 1 diabetes mellitus (T1DM) and IgA nephropathy (IgAN) to deepen understanding of the association between these two conditions and to provide a scientific basis for future preventive and therapeutic strategies. This study employed Mendelian randomization (MR) analysis, using single nucleotide polymorphisms (SNPs) derived from genome-wide association studies (GWAS) as genetic instrumental variables (IVs), to assess the association between T1DM and IgAN. The analytical approaches included univariable and multivariable MR, along with sensitivity analyses such as Mendelian randomization-Egger (MR-Egger) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), to evaluate the impact of heterogeneity and pleiotropy. Univariable MR analysis using the IVW method revealed an odds ratio (OR) of 1.009 [95% confidence interval (CI): 1.032-1.206] for the association between T1DM and IgAN. Adjusted results from multivariable MR analysis indicated a significant relationship between T1DM and increased risk of IgAN; for example, after adjusting for triglycerides (TG), the OR was 1.534 (CI: 1.213-1.543). After adjustment for HOMA-IR, the OR was 1.303 (CI: 1.149-1.198). Sensitivity analyses, including MR-Egger regression intercept testing (p = 0.476), suggested no pleiotropy, and MR-PRESSO did not detect any influence from outlier SNPs. The findings suggest that T1DM is a factor in increasing the risk of IgAN, enhancing our understanding of the potential relationship between T1DM and IgAN and providing possible biological pathways for future disease prevention and intervention.

The causal association of smoking, alcohol intake, and coffee intake with the risk of bacterial pneumonia: A Mendelian randomization study.

At present, the association of smoking, alcohol intake, and coffee intake with the risk of bacterial pneumonia (BP) remains controversial. In this study, we used a 2-sample Mendelian randomization (MR) analysis to estimate the association of smoking, alcohol intake, and coffee intake with the risk of BP. We extracted genetic variants associated with smoking initiation and cigarettes per day from the Genome-Wide Association Study and Sequencing Consortium of Alcohol and Nicotine Use database (944,625 individuals). We also extracted genetic variants associated with past tobacco smoking, alcohol intake frequency, and coffee intake from the UK Biobank database (1,316,166 individuals). BP outcomes were chosen from the FinnGen genome-wide association studies (GWAS) database (7987 patients and 188,868 controls). The inverse variance-weighted method was used primarily to calculate odds ratios (OR) and 95% confidence intervals (CI). Sensitivity analysis using different approaches such as weighted median, MR Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) have been implemented, as well as leave-one-out analysis to identify pleiotropy. The 2-sample MR analysis supported the causal association of genetically predicted cigarettes per day (OR: 1.23, 95% CI: [1.08-1.39], P < .01] and smoking initiation (OR: 1.22, 95% CI: [1.03-1.44], P = .02) with the risk of BP, but not past tobacco smoking, alcohol intake frequency, and coffee intake. Heterogeneity (P > .05) and pleiotropy (P > .05) tests provided confirmatory evidence for the validity of our MR estimates. Our findings provide relevant evidence for a favorable causal association of genetically predicted smoking initiation and cigarettes per day with BP risk. However, there may not be a causal association between past tobacco smoking, alcohol intake, and coffee intake with increased BP incidence rates.

Causal association between sarcopenia and cognitive impairment contributes to the muscle-brain axis: A bidirectional Mendelian randomization study.

There is a growing body of evidence suggesting a correlation between sarcopenia (SP) and cognitive impairment (CI), but with conflict. This study employed a bidirectional Mendelian randomization (MR) approach to ascertain the causality between SP and CI. This study looked at whether there might be causality between SP and CI by using a bidirectional MR analysis on the GWAS summary datasets, which anyone can publicly access. The primary analysis employed inverse variance weighting (IVW), with MR-Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) serving as supplements. Multiple sensitivity analyses were performed to enhance the stability of the results, which encompassed heterogeneity tests and pleiotropy tests. Appendicular lean mass (ALM), walking pace (WP), and grip strength (GS) were found to be causally connected to cognitive performance in forward MR analysis. In the reverse MR study, cognitive performance also had a causal impact on ALM and WP. Additionally, we discovered comparable outcomes in the replication samples, which strengthens the validity of our findings. The results of our MR investigation revealed a definitive cause-and-effect association between SP and CI. Our findings provide additional supporting evidence for the muscle-brain axis, which may suggest that muscle strengthening has a significant impact on the management and avoidance of CI. Geriatr Gerontol Int 2024; ••: ••-••.

Circulating inflammatory cytokines and the risk of cerebral small vessel disease: a bidirectional Mendelian randomization analysis

BackgroundA correlation between inflammation and cerebral small vessel disease (CSVD) has been hypothesized by earlier observational research, while this correlation has not been well established. Considering the significant clinical value of this causality determination, Mendelian randomization (MR) was implemented to investigate the causality between inflammatory cytokines and CSVD radiological lesions. MethodsUsing the publicly available Genome-Wide Association Study (GWAS) datasets, a bidirectional two-sample MR analysis was employed to infer causality between 91 inflammatory cytokines and CSVD phenotypes [white matter hyperintensity (WHM), fractional anisotropy (FA), mean diffusivity (MD), cerebral microbleeds (CMBs), and lacunar stroke]. A set of methods was used for sensitivity analysis, including Cochran's Q test, MR-Egger intercept method, and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Furthermore, the strength of causality was assessed using the Bonferroni correction. ResultsOur research discovered a mutually predictive bidirectional link between CSVD phenotypes and inflammatory cytokines. Following the application of the Bonferroni correction, fibroblast growth factor 21 (FGF-21) was significantly inversely correlated with an increased risk of CMBs (OR = 0.579, 95 % CI = 0.425-0.789, P = 0.00055). Using sensitivity analysis, heterogeneity, and horizontal pleiotropy were not detected. ConclusionIn this investigation, we established the causality between CSVD and inflammatory cytokines, with FGF-21 in particular significantly reducing the risk of CMBs. With further validation, these findings may provide new targets for the prevention, detection, and intervention of CSVD.

Causal association of serum vitamin D levels with urolithiasis: a bidirectional two-sample Mendelian randomization study.

In light of inconsistent evidence from previous observational studies regarding the correlation between serum vitamin D levels and urolithiasis, this study aimed to investigate the genome-wide causal association between genetically predicted serum 25(OH)D levels and urolithiasis using the Mendelian randomization (MR) approach. In this study, we utilized genome-wide association studies (GWAS) summary statistics from the UK Biobank and SUNLIGHT consortium for serum vitamin D levels, as well as urolithiasis data from FinnGen. We employed bidirectional two-sample MR analysis to evaluate potential causal relationships. The primary MR analysis relied on the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode approaches. Sensitivity analyses were conducted to ensure result robustness, including Cochran's Q test, MR-Egger intercept test, leave-one-out tests, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. The MR analysis indicated no significant causal effects of serum 25(OH)D levels on urolithiasis [IVW method: (kidney and ureteral stones: OR = 1.134;95% CI, 0.953 to 1.350, p = 0.155; lower urinary tract stones: OR = 1.158; 95% CI, 0.806 to 1.666, p = 0.428)]. However, according to the IVW results, genetically predicted kidney and ureteral stones were associated with decreased serum 25(OH)D levels (beta = -0.025; 95% CI, -0.048 to -0.003; p = 0.028), while they did not indicate a causal effect of lower urinary tract stones on serum 25(OH)D levels (beta = -0.002; 95% CI, -0.013 to -0.008; p = 0.662). A sensitivity analysis suggested the robustness of these causal associations. Our MR study did not provide evidence supporting a causal association between serum 25(OH)D levels and urolithiasis among individuals of European descent. However, there might exist a negative causal association between kidney and ureteral stones and serum 25(OH)D levels.

Hemoglobin levels in red blood cells and risk of colorectal cancer: A causal investigation based on Mendelian randomization.

Mean corpuscular hemoglobin (MCH) is a critical parameter in red blood cells, associated with various diseases. While studies suggest a potential link between MCH levels and colorectal cancer (CRC), observational studies are insufficient to establish causality directly. This study utilized a 2-sample Mendelian randomization (MR) approach to investigate the genetic causal relationship between MCH and colorectal cancer (CRC). Genome-wide association study (GWAS) summary data for both MCH and CRC were sourced from relevant databases. MR analyses were performed using methods including inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode. Cochrane's Q test was applied to assess heterogeneity in the MR findings. Horizontal pleiotropy was evaluated using the MR-Egger intercept test and the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Additionally, a leave-one-out analysis was conducted to assess the robustness of this association. The IVW method demonstrated that MCH is an independent risk factor for colorectal cancer (P = .013). Horizontal pleiotropy is unlikely to influence the causal relationship (P > .05), and there was no evidence of heterogeneity among the genetic variants (P > .05). Lastly, the leave-one-out test confirmed the stability and robustness of the association. All participants in the GWAS were derived from a specific population. Due to limitations inherent to the database, the Mendelian Randomization (MR) analysis was unable to incorporate stratified analyses by country, ethnicity, or age group.

Impact of gut microbiota on metabolic syndrome and its comprising traits: a two-sample mendelian randomization study

BackgroundThe prevalence of metabolic syndrome is on the rise globally. Understanding the etiology and discovering potential treatment target have become a priority. Observational data have linked gut microbiota with metabolic syndrome and its comprising traits. However, whether these relations underlie causal effects remains unclear.MethodsUsing Inver Variance Weighted (IVW) as primary analysis method, we performed two-sample Mendelian Randomization (MR) analyses to explore the causal relationship between gut microbiota and metabolic syndrome with its comprising traits. Methods including MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Weighted Mode, and Weighted Median were chosen for additional MR analysis to test the robustness of MR results. Cochran’s IVW Q test and leave-one-out IVW analysis tested the heterogeneity among instrumental variables (IVs). Steiger filtering was utilized to exclude all IVs with reverse causality. Genome-wide association study (GWAS) data used in this study were all from the largest respective GWAS studies available.ResultsOut of 1172 tests, a total of 16 associations with evidence of causality were identified after sensitivity analyses, but only 3 remained after multiple testing correction. Class Melainabacteria (β = 0.02, adjusted P = 0.01) with affiliated order Gastranaerophilales (β = 0.02, adjusted P = 1.20*10− 3) and genus Eubacterium hallii (β = 0.03, adjusted P = 0.03) showed a positive effect on abdominal obesity. All effect sizes were small (abs(β) < 0.1). All causal relationships identified were unidirectional.ConclusionsGiven the study’s limitations, we found little evidence supporting a large causal effect, i.e. absolute effect size > 0.1, of gut microbial taxa abundance on metabolic syndrome and its comprising traits. This study also suggests that previously reported associations between gut microbiota and metabolic syndrome with its comprising traits may not necessarily lead to causal relations.Clinical trial numberNot applicable.

Genetically Predicted Body Composition and Risk of Surgical Site Infection: A Mendelian Randomization Study.

Objective: This study employed uni-variable and multi-variable Mendelian randomization (MVMR) analyses, utilizing publicly available genome-wide association study (GWAS) data, to assess the causal relationship between body composition measures such as body mass index (BMI), waist circumference (WC), and the occurrence of surgical site infection (SSI). Patients and Methods: GWAS summary statistical data were obtained for BMI, WC, and SSI from the MRC Integrated Epidemiology Unit (MRC-IEU) database, inverse variance weighted (IVW) method was used as the main analysis, and supplement sensitivity analysis (including heterogeneity test, pleiotropy analysis, leave-one-out analysis, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO)) was used to check the robustness of the results. Results: The MR analysis showed that the increase in BMI and WC predicted by genes had a substantial causal effect on the incidence of SSI (IVW: odds ratio [OR] = 1.003, 95% confidence interval [CI] = 1.002-1.004, p < 0.001; IVW: OR = 1.003, 95% CI = 1.002-1.005, p < 0.001), respectively, and the MVMR analysis showed that after jointly incorporating smoking and alcohol parameters, the impact of BMI and WC on SSI remained substantial (OR = 1.003, 95% CI = 1.002-1.004, p < 0.001; OR = 1.004, 95% CI = 1.002-1.005, p < 0.001). Conclusion: We further support the causal relationship between increased body composition including BMI and WC and the occurrence of SSI, highlighting the importance of SSI prevention in patients with obesity. Further research is required to mitigate the occurrence of surgical incisions in patients with obesity in the future.

Association between human blood metabolome and risk of myocarditis: a mendelian randomization study

Myocarditis is a common disease of the cardiovascular and immune systems, but the relationship between relevant blood metabolites and the risk of myocarditis has not been well-established. To identify potential biometabolic markers associated with myocarditis, we conducted a two-sample Mendelian randomization (MR) study. We performed preliminary MR analysis using the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode methods to adjust for false discovery rate (FDR). Confounders were screened using the GWAS Catalog website. Sensitivity analyses included Cochrane Q-test, Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), scatterplots, funnel plots, and forest plots. For genetic and directional analysis, we employed co-localization analysis and the Steiger test. MR analysis was performed using the FinnGen database and meta-analysis was performed using the IEU database. MR analysis identified significant correlations for five metabolic biomarkers after FDR correction. These included four known metabolites: kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, and 5-acetylamino-6-formylamino-3-methyluracil, as well as one unknown metabolite, X-25,422. Among these, kynurenine (OR = 1.441, 95%CI = 1.089–1.906, p-value = 0.018) and 1-stearoyl-GPE (18:0) (OR = 1.263, 95%CI = 1.029–1.550, p-value = 0.029) were identified as risk factors for myocarditis, while deoxycarnitine (OR = 0.813, 95%CI = 0.676–0.979, p-value = 0.029), 5-acetylamino-6-formylamino-3-methyluracil (OR = 0.864, 95% CI = 0.775–0.962, p-value = 0.018), and X-25,422 (OR = 0.721, 95%CI = 0.587–0.886, p-value = 0.009) were found to be protective factors. No evidence of heterogeneity, horizontal pleiotropy, or sensitivity issues was observed, and no shared genetic factors between exposure and outcome were detected. The causality was in the correct direction. Meta-analysis further confirmed the causal relationship between the five metabolites and myocarditis. This study identifies a causal relationship between five circulating metabolites and myocarditis. Kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, X-25,422, and 5-acetylamino-6-formylamino-3-methyluracil may serve as potential drug targets for myocarditis, providing a theoretical basis for the prevention, diagnosis, and treatment of the condition.

Physical activities and breast cancer: a Mendelian randomization study

IntroductionPrevious research suggests a potential association between physical activity (PA) and breast cancer (BC), but the causal relationship remains uncertain. The aim of this study was to explore the causal relationship between PA and BC through Mendelian randomization (MR) analysis.Material and methodsGenome-wide association studies utilizing data from the UK Biobank baseline were employed to analyze PA phenotypes, encompassing 460,376 participants. Summary data for BC, comprising 122,977 cases and 105,974 controls, were obtained from the BC Association Consortium. The cases were further categorized based on estrogen receptor status into estrogen receptor-positive breast cancer (ER+ BC) and estrogen receptor-negative breast cancer (ER– BC). The inverse variance weighted method was employed as the primary approach for two-sample MR. Additionally, the MR-PRESSO (MR-Pleiotropy RESidual Sum and Outlier) method was utilized to eliminate outliers. Tests for heterogeneity and pleiotropy were conducted to enhance result accuracy. Furthermore, multivariable Mendelian randomization was performed, adjusting for potential confounders to ensure result stability.ResultsMR analysis was employed to assess the causal link between PA and BC. Two-sample MR analysis revealed a genetic prediction indicating that walking for pleasure was associated with decreased risk of ER+ BC (odds ratio (OR) = 0.302, 95% CI = 0.105–0.872, p = 0.027), while other physical activities were not significantly correlated with BC, ER+ BC and ER– BC. These findings remained reliable and consistent in the sensitivity analysis, including Cochran’s Q and MR-Egger regression. Furthermore, reverse MR analysis suggested that BC did not exert a notable impact on PA.ConclusionsOur findings suggest that engaging in leisure walking is associated with a reduced risk of ER+ BC. Nevertheless, additional research is warranted to comprehensively elucidate the underlying mechanisms and strengthen the causal relationship.

Causal association between non-thyroidal autoimmune diseases and Graves' ophthalmopathy: a mendelian randomization study

PurposeThis Mendelian randomization (MR) analysis study aimed to investigate the genetic causal relationship between non-thyroidal autoimmune diseases (ADs) and Graves' ophthalmopathy (GO). MaterialsSingle nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis vulgaris (PV), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) were obtained from the IEU Open genome-wide association studies (GWAS) database, GWAS data for GO were obtained from the FinnGen database. Bidirectional MR analysis was conducted using inverse variance weighted (IVW) method, weighted median (WM) method and MR-Egger test. Cochran's Q statistic was used to assess the heterogeneity between SNP estimates. MR-Egger regression was used to evaluate horizontal pleiotropy and MR pleiotropy residual sum and outlier (MR-PRESSO) test was used to detect the outliers. ResultsFor non-thyroidal ADs, the forward MR results using the IVM method showed that T1D (OR=1.259, 95%CI 1.026-1.5465; p=0.028) and SLE (OR=1.807, 95%CI 1.229-2.655; p=0.003) were correlated with the risk of GO at the genetic level, while there was no evidence showing that IBD, MS, PV and RA were correlated with GO. In the reverse MR study, there was a significant increase in the risk of developing T1D in GO (OR=1.135, 95%CI 1.018-1.265; p=0.022), but pleiotropy and heterogeneity existed. ConclusionIn the European population, there is strong genetic evidence that patients with T1D and SLE have a higher risk of developing GO, whereas the effect of GO on ADs is unclear.

Dissecting Causal Relationships Between Dietary Habits and Diverse Subtypes of Stroke: Mendelian Randomization Study

Background: Understanding the causal relations between dietary habits and stroke is crucial for prioritizing public health interventions and developing effective health strategies. This study utilized Mendelian randomization (MR) analysis to examine the causal associations between 20 dietary habits and various stroke subtypes, aiming to identify potential mediators and evaluate the proportions of mediation. Methods: A two-sample MR analysis was conducted to examine the causal relationships between dietary habits and stroke incidence. Mediation analysis, two-step MR (TSMR), and multivariable MR (MVMR) were employed to identify potential mediators. Genetic data pertaining to dietary habits and stroke were obtained from extensive genome-wide association study (GWAS) consortia. The inverse variance-weighted (IVW) method served as the primary analytical approach, with the additional scrutiny of significant correlations conducted through the Egger regression, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and weighted median techniques. Results: Our analyses indicated that genetically predicted intakes of dried fruits, cheese, cereal, oily fish, and hot drink temperatures were protective against stroke, whereas higher intakes of lamb/mutton, poultry, and added salt significantly elevated stroke risk. Specifically, dried fruit consumption demonstrated a protective effect against total stroke (β = −0.009, p = 0.013), ischemic stroke (β = −0.475, p = 0.003), and small-vessel ischemic stroke (β = −0.682, p = 0.033) through reductions in BMI levels, accounting for mediated proportions of 3.2%, 17.1%, and 8.5%, respectively. Furthermore, cheese intake provided a protective effect against ischemic stroke (β = −0.275, p = 0.003) by decreasing BMI and increasing HDL-C levels, with mediated proportions of 30.5% and 6.5%. Together, BMI and HDL-C accounted for 34.9% of the beneficial effect of cheese intake on reducing the risk of ischemic stroke. In contrast, an increased salt intake exhibited a positive association with large-artery ischemic stroke (β = 0.432, p = 0.033) through BMI elevation, with a mediated proportion of 10.9%. Conclusions: Our findings provide compelling evidence supporting causal relationships between dietary habits and stroke subtypes, while identifying mediators and evaluating the proportions of mediation. Adhering to a low-calorie, nutrient-dense diet enriched with dried fruits, cheese, and cereal, along with reduced salt and poultry consumption, could potentially mitigate stroke risk.

Impulsivity and epilepsy: a bidirectional mendelian randomization study

BackgroundPrevious studies have found that patients with epilepsy are more likely to suffer impulsivity. However, the causal relationship between impulsivity and epilepsy is unknown. In this study, we conduct a bidirectional Mendelian randomization (MR) study to explore the causal relationship between impulsivity and epilepsy with recurrent seizure.MethodsData of the genome-wide association studies (GWAS) on 14 impulsivity traits and epilepsy were obtained from the GWAS catalog and UK Biobank. Inverse-variance weighted (IVW) and weighted median (WM) methods were utilized for MR estimates. IVW, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were used to assess heterogeneity and pleiotropy.ResultsSingle-nucleotide polymorphisms (SNPs) related to the lack of perseverance were associated with a decreased risk of epilepsy with recurrent seizures according to the results of IVW (odd ratio [OR] = 0.93, 95% confident interval [CI] = 0.90–0.97, P = 0.001) and WM (OR = 0.93, 95%CI = 0.87–0.98, P = 0.007). Meanwhile, heterogeneity was not observed with a Cochran Q-derived P value of 0.819 for MR egger and a P value of 0.808 for IVW. Pleiotropy was not found according to the MR-PRESSO (P = 0.273). The other 13 impulsivity traits had no causal effect on epilepsy with recurrent seizures. Meanwhile, SNPs related with epilepsy with recurrent seizures had no causal effect on the 14 impulsivity traits.ConclusionsThis MR study suggests that lack of perseverance may be a protective factor against epilepsy with recurrent seizures. However, epilepsy with recurrent seizures does not affect impulsivity.

The Association between Non-Alcohol Liver Fatty Disease and Coronary Artery Calcification: A Two-Sample Mendelian Randomization Study.

Although prior observational studies have suggested that patients with non-alcohol fatty liver disease (NAFLD) may have a higher risk of coronary artery calcification (CAC), these findings remain controversial. This study aimed to explore the causal association between NAFLD and CAC at genetic level by two-sample Mendelian randomization (MR) analysis. Utilizing summary-level data from multiple large-scale genome-wide association studies (GWAS) in European populations, a two-sample MR analysis was initially conducted to explore the potential causal association between NAFLD and CAC. The results of the MR analysis were pooled through random-effect meta-analysis. The inverse variance weighting (IVW) method served as the primary approach for MR analysis. Additionally, the weighted median, MR-Egger and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods was applied for sensitivity analysis. Summary-level data on liver fatty content was utilized for validation analysis, while summary-level data on cirrhosis served as positive control, further ensuring the validity and robustness of our findings. Reverse MR analysis was performed to assess the association between CAC and NAFLD, employing instrument variables derived from CAC. The MR analysis indicated that genetically predicted NAFLD had no effects on the risk of CAC (Beta: 0.01, 95% CI: -0.02 to 0.03, P = 0.74). Likewise, the reverse MR analysis found no significant genetic association between CAC and NAFLD (OR: 1.00, 95% CI: 0.96 to 1.06, P = 0.88). Validation analysis yielded consistent results, showing no significant association between fatty liver content and CAC. Our two-sample MR analysis did not support that there is a causal association between NAFLD and CAC at genetic level. The association between NAFLD and CAC reported in some previous observational studies may rely on NAFLD complicated with metabolic disorders, rather than being directly linked to the hepatic steatosis.

A Mendelian randomization study of the association between serum uric acid and osteoporosis risk.

The relationship between serum uric acid (SUA) and osteoporosis (OP) has yielded conflicting results in observational studies. This Mendelian randomization (MR) study aims to elucidate the causal association between SUA and OP. A two-sample MR analysis was conducted using summary-level data from genome-wide association studies (GWAS). Two sets of polygenic instruments strongly associated (p < 5 × 10-8) with SUA were extracted from the CKDGen consortium and UK biobank. Polygenic instruments associated with OP (p < 5 × 10-8) were derived from FinnGen biobank and UK biobank. Inverse variance weighting (IVW) was employed as the primary analysis method. Additionally, we utilized MR-Egger, weighted median, the simple mode method, and the weighted mode as complementary analyses. Cochran's Q statistics were used to assess heterogeneity, with MR-Egger intercept testing and MR pleiotropy residual sum and outlier (MR-PRESSO) to examine horizontal pleiotropy. Sensitivity analysis was performed using the leave-one-out method. The IVW analysis conducted across four groups confirms no significant causal relationship between SUA concentration and OP: UKB-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.464), CKD-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.349), UKB-Fin (OR: 0.934, 95% CI: 0.747-1.168, p=0.549), CKD-Fin (OR: 1.041, 95%CI: 0.934-1.161, p=0.470). Furthermore, additional four MR analyses corroborated these findings. Upon excluding all outliers identified by the MR-PRESSO test, no significant directional pleiotropy was observed, except for some data heterogeneity noted in the UKB-UKB group (Q=50.65, P=0.002). Additionally, a leave-one-out analysis indicated that no single SNP exerted undue influence on the results. This MR analysis provides convincing genetic evidence that there is no causal association between SUA and OP, SUA is unlikely to increase or reduce the risk of OP.

Causal Association of Chronic Venous Insufficiency and Cardiovascular Diseases: A Univariable and Multivariable Mendelian Randomization Study.

The causal relationship between chronic venous insufficiency (CVI) and cardiovascular diseases (CVDs) has yet to be elucidated. Herein, we implement Mendelian randomization (MR) analysis to investigate the causal association. A two-sample MR approach using genetic data from FinnGen and genome-wide association studies (GWAS) Catalog was applied to investigate the causal relationship between CVI and CVDs. This study assessed 77 single nucleotide polymorphisms (SNPs) as instrumental variables, employing random-effect inverse-variance-weighted MR, weighted median, Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and Robust Adjusted Profile Score (RAPS) methods. Multivariable MR (MVMR) considered confounding factors. Genetically predicted CVI was associated with reduced heart failure risk (odds ratio (OR) = 0.96, 95% confidence interval (95% CI): 0.93-0.99, p = 0.025) and increased atrial fibrillation risk (OR = 1.06, 95% CI: 1.03-1.09, p = 0.0002). MVMR, adjusting for venous thromboembolism (VTE), lower limb ulceration, obesity, smoking, and alcohol, attenuated these associations. No significant links were found with hypertension, aortic aneurysm, coronary artery disease, myocardial infarction, valvular heart disease, or stroke. This MR study supports an association between CVI and CVDs, which may imply CVI should be monitored during the treatment of heart failure and atrial fibrillation.

Causality between diabetes and membranous nephropathy: Mendelian randomization.

Membranous nephropathy (MN) has not yet been fully elucidated regarding its relationship with Type I and II Diabetes. This study aims to evaluate the causal effect of multiple types of diabetes and MN by summarizing the evidence from the Mendelian randomization (MR) study. The statistical data for MN was obtained from a GWAS study encompassing 7979 individuals. Regarding diabetes, fasting glucose, fasting insulin, and HbA1C data, we accessed the UK-Biobank, within family GWAS consortium, MAGIC, FinnGen database, MRC-IEU, and Neale Lab, which provided sample sizes ranging from 17,724 to 298,957. As a primary method in this MR analysis, we employed the Inverse Variance Weighted (IVW), Weighted Median, Weighted mode, MR-Egger, Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) and Leave-one-out sensitivity test. Reverse MR analysis was utilized to investigate whether MN affects Diabetes. Meta-analysis was applied to combine study-specific estimates. It has been determined that type 2 diabetes, gestational diabetes, type 1 diabetes with or without complications, maternal diabetes, and insulin use pose a risk to MN. Based on the genetic prediction, fasting insulin, fasting blood glucose, and HbA1c levels were not associated with the risk of MN. No heterogeneity, horizontal pleiotropy, or reverse causal relationships were found. The meta-analysis results further validated the accuracy. The MR analysis revealed the association between MN and various subtypes of diabetes. This study has provided a deeper understanding of the pathogenic mechanisms connecting MN and diabetes.

Association Between Serum Galectin-3 and Parkinson's Disease: A Two-Sample Mendelian Randomization Study.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with poor prognosis. Observational studies have demonstrated a significant correlation between serum galectin-3 and PD, suggesting a potential role of galectin-3 as a biomarker for PD. However, it is still unclear whether galectin-3 contributes to the risk of the disease. A two-sample Mendelian randomization (MR) approach was used in this study. Genetic instruments for serum galectin-3 level were selected from a genome-wide association study (GWAS), including 30,931 European individuals. Summary-level statistics for PD were derived from another published GWAS, including 33,674 cases and 449,056 controls. Primary analysis was conducted using the inverse-variance weighting (IVW) method. Weighted median, MR-Egger, simple mode, weighted mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were used as complementary analyses. To detect heterogeneity, Cochran's Q statistic and leave-one-out analysis were used. For testing potential horizontal pleiotropy, the MR-Egger intercept test and MR-PRESSO global test were conducted. MR analysis using IVW model (OR 1.112, 95% CI 1.025-1.206, p = 0.010), weighted median (OR 1.135, 95% CI 1.037-1.242, p = 0.006), weighted mode (OR 1.142, 95% CI 1.038-1.257, p = 0.030), and MR-PRESSO (OR 1.112, 95% CI 1.046-1.182, p = 0.012) presented a consistent result, indicating that increased serum galectin-3 was associated with a higher risk of PD. No heterogeneity or horizontal pleiotropy was detected in the analyses. The study shows a suggestive association between galectin-3 and PD. Increasing serum galectin-3 was associated with an increase in PD risk. Galectin-3 may play an important role in the causal pathway to PD.

Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.

Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. 91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.