Mendelian Randomization Pleiotropy Residual Sum Research Articles

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.

Investigation of the Association Between Hyperlipidemia and Ossification of The Posterior Longitudinal Ligament Through Two-Sample Mendelian Randomization Analysis.

A Two-Sample Mendelian Randomization Analysis. This study aimed to investigate the association between genetically predicted hyperlipidemia and ossification of the posterior longitudinal ligament (OPLL) using two-sample Mendelian randomization (MR) analysis. Several observational studies suggested associations between hyperlipidemia and OPLL. Genome-wide association study (GWAS) summary statistics for hyperlipidemia and OPLL were retrieved from the public database. The MR analysis employed the Inverse Variance Weighted (IVW) method, which was supplemented by MR-Egger, weighted median, and weighted mode analyses. Sensitivity analyses, incorporating Cochran's Q test, MR-Egger regression and the MR pleiotropy residual sum and outlier test, additionally assessed the robustness of the findings. The IVW analysis revealed a significant association between total cholesterol levels and OPLL (OR: 1.44,95% CI:1.06-1.96, P=0.02). Similarly, a significant association was observed between LDL cholesterol and OPLL (OR: 1.31,95%CI:1.05-1.63, P=0.02). Supplementary analyses further supported the significant association of total cholesterol levels and LDL cholesterol on OPLL (P <0.05). In sensitivity analyses, LDL cholesterol exposure showed robust results, with no outliers detected by loo or mrpresso, despite MR-Egger hints at pleiotropy. For total cholesterol exposure, MR-Egger suggested no pleiotropy, though heterogeneity and outliers were present. Outlier removal confirmed the initial positive association, underlining study stability. However, no significant associations were found of hyperlipidemia, triglycerides, HDL cholesterol on OPLL. This study suggests a association of total cholesterol levels and LDL cholesterol levels on OPLL. Further research is warranted to validate these findings and explore potential therapeutic implications.

Changes in resting-state functional connectivity of large-scale brain networks in bulimia nervosa: evidence from causal analysis.

Bulimia nervosa (BN) has been observationally linked to the functional connectivity (FC) of large-scale brain networks, but the biological mechanisms remain unclear. This study used two-sample Mendelian randomization (MR) with genetic variations as instrumental variables (IVs) to explore potential causal relationships between FC and BN. Summary data from genome-wide association studies (GWAS) involving 2,564 individuals were analyzed to identify genetically predicted BN. Functional magnetic resonance imaging parameters and materials were sourced from the UK Biobank. The variables underwent independent component analysis processing by the database to generate the final GWAS dataset. Various methods, including MR Pleiotropy RESidual Sum and Outlier, MR Egger, and weighted median, were employed to detect heterogeneity and pleiotropy, with inverse variance weighting serving as the principal estimation method (P < 0.05). The FC imaging-derived phenotypes revealed that BN exerted a causal influence on the FC between large-scale networks, including the visual network, default mode network (DMN), frontoparietal network, somatosensory network (SSN), and ventral attention network. Additionally, BN had a causal impact on the within-network FC of both the DMN and SSN. The study provides evidence that BN leads to further changes in FC patterns within and between large-scale brain networks.

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.

Genetically Predicted Sleep Traits and Sensorineural Hearing Loss: A Mendelian Randomization Study.

Observational studies suggest a potential association between sleep characteristics, sensorineural hearing loss (SNHL), and sudden SNHL (SSNHL), but causal evidence is scarce. We sought to clarify this issue using two-sample Mendelian randomization analysis. The inverse-variance weighted (IVW) method was performed as primary analysis to assess bidirectional causal associations between sleep traits (chronotype, sleep duration, insomnia, daytime sleepiness, and snoring) and SNHL/SSNHL using publicly available Genome-Wide Association Studies summary data from two large consortia (UK Biobank and FinnGen). Sensitivity analyses, including Mendelian randomization (MR)-Egger, Mendelian randomization pleiotropy residual sum and outlier, weight median, Cochran's Q test, leave-one-out analysis, and potential pleiotropy analysis, were conducted to ensure robustness. IVW analysis found suggestive associations of morning chronotype (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.01-1.16, p = 0.031) and daytime sleepiness (OR = 1.88, 95% CI = 1.24-2.87, p = 0.003) with SNHL onset. Additionally, morning chronotype was nominally associated with SSNHL onset using IVW method (OR = 1.37, 95% CI = 1.10-1.71, p = 0.006). However, there was no evidence for the causal effect of SNHL and SSNHL on different sleep traits (all p > 0.05). Sensitivity analysis showed that the results were stable. Within the MR limitations, morning chronotype and daytime sleepiness were underlying causal contributors to the burden of SNHL, indicating that optimal sleep might facilitate the prevention and development of SNHL. 3 Laryngoscope, 134:4723-4729, 2024.

The role of digital device use on the risk of migraine: a univariable and multivariable Mendelian randomization study.

The pervasive integration of digital devices into daily life has raised concerns about their potential health impacts. This study aimed to explore the causal relationships between digital device use and the risk of migraine using Mendelian randomization (MR). Genetic data on digital device use and migraines were sourced from large-scale genome-wide association studies conducted by the UK Biobank, the FinnGen study, and the International Headache Genetics Consortium. Univariable MR (UVMR), meta-analysis, and multivariable MR (MVMR) approaches were conducted to explore and verify the causal effects of digital device use (including mobile phone use, computer use, playing computer games, and watching television) on migraine risk. Sensitivity analyses were conducted using Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Radial, MR Steiger, and leave-one-out methods. UVMR analyses revealed that genetically predicted mobile phone use was significantly associated with an increased risk of overall migraine (odds ratio [OR] = 2.39, p = 9.78e-5) and migraine without aura (MO) (OR = 2.25, p = 0.024). Additionally, there were significant positive associations between genetically predicted television watching and the risk of overall migraine (OR = 1.63, p = 2.12e-5) and MO (OR = 2.10, p = 4.98e-5). These results were further supported by the meta-analysis and MVMR analysis. Sensitivity analysis indicated no heterogeneity or pleiotropy. This comprehensive MR study provides preliminary evidence for the causal impact of mobile phone use and television watching on the risk of migraines. Further studies are needed to explore these associations across different populations.

Genetic Estimates of Correlation and Causality Between Keratoconus and Osteoarthritis.

The relationship between keratoconus (KC) and osteoarthritis (OA) has been hypothesized, yet the causal link remained obscure. We aimed to evaluate the genetic correlation and causality between KC and OA through a genetic perspective. Linkage Disequilibrium Score Regression and bidirectional 2-sample Mendelian randomization (MR) analysis were conducted. Data were used from genome-wide association study on KC (4669 cases and 116,547 controls), OA (encompassing 24,955 patients with knee OA, 15,704 patients with hip OA, 39,427 patients with knee or hip OA, and 378,169 control participants), and KC data in the FinnGen consortium for replication and meta-analysis. Simple model, weighted model, inverse-variance weighted, weighted median, and MR-Egger regression were employed to assess the causal effects. MR pleiotropy residual sum and outlier method, MR-Egger method, and leave-one-out analysis were also applied to detect pleiotropy. No statistically significant genetic correlation between KC and OA (all P > 0.05) were observed. MR estimates obtained from all 5 methods after meta-analysis revealed nonsignificant odds ratio values of KC-related traits to knee OA, hip OA, and OA (all adjusted P > 0.05). No evidence of causal relationships of knee and hip OA with KC-related traits was detected after meta-analysis of all 5 MR methods (all adjusted P > 0.05). The large MR analysis indicated that KC may not be causally associated with a risk of OA.

Association between venous thromboembolism and atrial fibrillation: a Mendelian randomization study

BackgroundAlthough previous observational studies have shown an association between venous thromboembolism (VTE) and atrial fibrillation (AF), the underlying causal relationship between them remains uncertain.Methods and resultsThis two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal relationship between VTE and AF. The VTE dataset were obtained from FinnGen, including 9,176 cases and 209,616 controls. Meanwhile a genome-wide association study (GWAS) of 60,620 individuals with AF and 970,216 control subjects identified genetic variations associated with AF. The principal MR analytic approach used in this study is the inverse-variance weighting (IVW) method. Furthermore, we performed complementary MR analyses, including the MR-Egger, Weighted median (WM), and Weighted Mode. MR pleiotropy residual sum was applied to identify pleiotropy. The MR analysis showed suggestive causal associations between VTE and the risk of AF (p = 0.0245, OR [95%CI]: 1.027 [1.003, 1.051]). The reverse MR analysis found that genetic susceptibility to AF was not significantly associated with VTE, as determined by the IVW method (p = 0.7773). The robustness of these findings was corroborated through MR sensitivity analyses.ConclusionsThere is a unidirectional causal relationship between VTE and AF, meaning that VTE is a causal risk factor for AF, whereas no effect of AF on VTE was identified.

Genetic evidence supporting the causal role of 25-hydroxyvitamin D levels in the prognosis of ER- breast cancer: A Mendelian randomization study.

This study aims to investigate the connection between 25-hydroxyvitamin D (25(OH)D) levels and the prognosis of breast cancer with various estrogen receptor (ER) statuses. The summary statistics of 25(OH)D levels was obtained from a GWAS of 441,291 individuals and the information of breast cancer was collected from the Breast Cancer Association Consortium. We analyzed the causal association between 25(OH)D levels and breast cancer prognosis using a number of approaches, including inverse variance weighting (IVW). The heterogeneity test was performed using Cochran Q test. IVW, Mendelian randomization (MR)-Egger, and MR Pleiotropy RESidual Sum and Outlier methods were used for sensitivity analysis. In addition, a multivariate MR adjusted for total triglycerides, total cholesterol, and body mass index was used for further analysis. Two-sample MR results showed that 25(OH)D levels were not associated with prognosis in overall breast cancer (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.73-1.19, IVW exam) and estrogen receptor positive (ER+) breast cancers (OR = 1.12, 95% CI = 0.77-1.63, IVW exam) and were protective associated with prognosis in estrogen receptor negative (ER-) breast cancers (OR = 0.55, 95% CI = 0.34-0.87, IVW exam). Sensitivity analysis did not observe the presence of heterogeneity and horizontal pleiotropy. In multivariate MR analysis, after adjusting for total triglycerides, total cholesterol, and body mass index, the correlation between the protective relationship between 25(OH)D levels and the prognosis for ER- breast cancer remained and became increasingly significant (OR = 0.51, 95% CI = 0.31-0.83, P = .007). This study demonstrated a protective relationship between 25(OH)D levels and the prognosis of ER- breast cancer, but there was no connection between 25(OH)D levels and the prognosis of ER+ breast cancer.

Educational attainment, brain cortical structure, and sarcopenia: a Mendelian randomization study.

Previous observational studies have suggested associations between high-level educational attainment (EA) and a lower risk of sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. The protective effect of EA on sarcopenia may be mediated via changes in brain cortical structure. The aim of this study was to use a two-step Mendelian randomization (MR) analysis to illustrate the causal relationship between EA, brain cortical structure, and sarcopenia. Instrumental variables at the genome-wide significance level were obtained from publicly available datasets, and inverse variance weighted as the primary method was used for MR analysis. We perform several sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analyses, and MR Pleiotropy Residual Sum and Outlier to evaluate the reliability of the results. EA was causally associated with increased appendicular lean mass (β = 0.25, 95% confidence interval (CI): 0.19 to 0.31, p = 2.25 × 10-15), hand grip strength (left: β = 0.042, 95% CI: 0.013 to 0.071, p = 4.77 × 10-3 and right: β = 0.050, 95% CI: 0.022 to 0.079, p = 5.17 × 10-4), and usual walking pace (β = 0.20, 95% CI: 0.18 to 0.22, p = 6.16 × 10-83). In addition, EA was associated with increased brain cortical surface area (β = 4082.36, 95% CI: 2513.35 to 5681.38, p = 3.40 × 10-7) and cortical thickness (TH) (β = 0.014, 95% CI: 0.0045 to 0.023, p = 3.45 × 10-3). Regarding the causal effect of EA on usual walking pace, the mediatory effect of TH was 0.0069 and the proportion of mediation by TH was 3.43%. The study will have revealed the protective causal effect of EA on sarcopenia, which provides a reference for the prevention of sarcopenia at the public health level. We also will have found EA could affect the brain cortical structure, and the brain cortical structure could mediate the protective effect of EA against sarcopenia risk.

Relationships between heart failure, depression, and anxiety: A Mendelian randomization study.

Growing evidence suggests that heart failure (HF) is associated with an increased risk of depressive disorders and anxiety. However, the existing studies were observational and may have confounded and not reflected true causal relationships. This study collected genetic instruments about HF, depression, and anxiety from publicly available genetic summary data. Two-sample Mendelian randomization (MR) analysis was performed, with inverse-variance weighted designated as the primary approach for determining causal effects. Secondary analyses included MR-Egger regression and the weighted media method. Additionally, we conducted MR pleiotropy residual sum and outlier to address horizontal pleiotropy. Cochran Q test, MR-Egger intercept test, and leave-one-out analysis were used to assess the robustness of the findings. The significance is determined by a P-value below .05. Gene prediction result revealed that HF did not exhibit a significant association with elevated incidence of depression by inverse-variance weighted method no matter HF from the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.93-1.18, P = .424 for major depressive disorder, MDD; OR = 1.01, 95% CI = 0.94-1.09, P = .782 for major depression) or the FinnGen Consortium (OR = 1.03, 95% CI = 0.92-1.15, P = .644 for MDD; OR = 1.00, 95% CI = 0.94-1.07, P = .962 for major depression). In contrast, the results of HF on anxiety exhibited inconsistency (OR = 1.60, 95% CI = 1.10-2.31, P = .013 for Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium; OR = 1.42, 95% CI = 0.91-2.21, P = .123 for FinnGen Consortium); however, a combined effect analysis indicated support causal relationship between HF and the risk of anxiety (OR = 1.52, 95% CI = 1.07-2.00, P < .001). Our findings did not reveal evidence to confirm a causal association between HF and depression. However, our results provide support for a causal effect of HF on the risk of anxiety.

Genetic association of gut microbiota with osteoarthritis: a multivariable Mendelian randomization study considering medication use.

Background. The interplay among human gut microbiota (GM) composition, osteoarthritis (OA) and OA-related medication use has been extensively discussed. However, to date, there has been no exploration of the genetic correlation among these three factors.Hypothesis/Gap. The potential causal link between GM and OA), and whether medications influence this relationship, remains unclear.Methods. We utilized bidirectional Mendelian randomization (MR) to explore the genetic associations between GM and OA. We leveraged genome-wide association study (GWAS) summary statistics from the MiBioGen and GO consortia, which provided data on GM taxa and OA cases, respectively. We identified outlier single-nucleotide polymorphisms using radial-MR and assessed causal associations using inverse variance weighting (IVW), weighted median and MR-Egger methods. Robust outcomes, consistent across these methods, were reported. We addressed potential biases through tests for horizontal pleiotropy and heterogeneity, supplemented by the Mendelian randomization pleiotropy residual sum and outlier method. Multivariable MR techniques were applied to adjust for OA medication use using UK Biobank data.Results. IVW estimates revealed a significant increase in hip OA risk for Gordonibacter and Eubacterium (brachy group) [odds ratio (OR): 1.09, 95% confidence interval (CI): 1.04-1.15, P=7.82E-04; OR: 1.09, 95% CI: 1.03-1.16, P=4.67E-03, respectively]. Conversely, Senegalimassilia, Slackia and Streptococcus exhibited protective effects (OR: 0.88, P=2.14E-02; OR: 0.88, P=3.33E-02; 0.91, P=4.29E-02). Sutterella increased the risk of knee OA (OR=1.15, 95% CI: 1.07-1.25, P=4.06E-04), while Haemophilus decreased it (OR=0.94, 95% CI: 0.88-1.00, P=4.26E-02). No significant heterogeneity or horizontal pleiotropy was observed in the results. Even after accounting for the potential confounding effect of medication, the results remained consistent. No reverse causation was detected.Conclusions. Our MR study reveals gut microbiome links to OA risk. Associations hold after adjusting for medication, indicating a potential causal connection between GM and OA.

Association of cardiovascular disease and urate levels with aortic aneurysm: a bilateral mendelian randomization study

The aim of this study is to investigate the potential causal relationships between coronary artery disease (CAD), myocardial infarction (MI), urate levels, and aortic aneurysm (AA), abdominal aortic aneurysm (AAA), thoracic aortic aneurysm(TAA), aortic dissection (AD) in individuals of European ancestry. To examine the potential causal relationships between CAD, MI, and urate levels with AA, AAA, TAA, AD, respectively, we performed a two-sample Mendelian randomization (MR) analysis. Genetic instruments that reached genome-wide significance (p < 5 × 10 − 8) for risk factors were obtained from genome-wide association studies(GWASs) conducted on individuals of European origin. On the other hand, genetic instruments of AA, AAA, TAA or AD were chosen from the FinnGen cohort. The primary analysis employed the inverse-variance weighted MR method, while sensitivity analyses were conducted using MR-Egger, weighted median MR, MR pleiotropy residual sum and outlier, and Phenoscanner searching. In addition, we performed the MR-Egger intercept analysis to identify potential pleiotropy and utilized Cochran’s Q statistics to evaluate heterogeneity. Additionally, we conducted bidirectional Mendelian randomization experiments to mitigate the potential influence of reverse causation. According to the results of our study, there were statistically significant higher risks for AA in relation to CAD/MI(odds ratio (OR) with 95% confidence interval (CI): 1.309 (1.150–1.490), and 1.255 (1.147–1.373). Similarly, there were statistically significant higher risks for AAA in relation to CAD and MI (OR with 95% CI: 1.383 (1.189–1.609), and 1.352 (1.178–1.552). The sensitivity analysis demonstrated that the causative effects of CAD/MI, and AA /AAA, were robust. A positive causal link was observed between CAD/MI, and AA/AAA. Nevertheless, no causal link was found between CAD, MI, urate levels, and TAA .

The causal effects of inflammatory bowel disease on skin carcinoma: A two-sample Mendelian randomization study.

Observational studies have indicated that inflammatory bowel disease (IBD) patients have higher incidence of skin carcinoma (SC), including melanoma skin carcinoma (MSC) and nonmelanoma skin carcinoma (NMSC) than healthy people. However, whether there is a causal relationship between the 2 is unclear. The purpose of this study was to evaluate the causality of IBD on SC using the Mendelian randomization (MR) analysis. We performed a two-sample MR analysis using publicly available genome-wide association study data. Eligible instrumental variables were selected based on the 3 core assumptions of MR analysis. The inverse-variance weighted (IVW) approach served as the primary analytical method. Supplementary analyses were conducted using MR-Egger regression, the weighted median, the weighted mode, and MR pleiotropy residual sum and outlier methods. Genetically predicted IBD (IVW odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.02-1.13, P = .011) and ulcerative colitis (UC; IVW OR = 1.09, 95% CI: 1.03-1.16, P = .003) were associated with an increased risk of MSC. Results of complementary methods were consistent with those of the IVW method with the exception of the weighted mode. In addition, Crohn disease (CD; IVW OR = 1.04, 95% CI: 0.99-1.08, P = .128) did not have a causal effect on MSC. Moreover, IBD (IVW OR = 1.03, 95% CI: 1.00-1.07, P = .034) and CD (IVW OR = 1.03, 95% CI: 1.00-1.06, P = .045) were associated with an increased risk of NMSC. However, UC (IVW OR = 1.00, 95% CI: 0.97-1.04, P = .803) was not significantly associated with an increased risk of NMSC. Our study revealed genetically predicted associations between IBD and the risks of MSC and NMSC in European populations. Furthermore, UC was associated with an increased risk of MSC, while CD was associated with a higher risk of NMSC. However, the potential influence of immunosuppressive agents or biologics cannot be excluded.

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.

The Relationship between Negative Emotions and Atrial Fibrillation: A Mendelian Randomization Study.

The relationship between negative emotions and atrial fibrillation (AF) has garnered significant attention, yet observational studies have yielded contradictory findings regarding the causal associations between the two. Our study sought to provide genetic evidence for a causal relationship between negative emotions and AF through Mendelian randomization (MR) study. Utilizing genetic variations associated with negative emotions and AF as instrumental variables (IVs), a two-sample MR study was implemented. The potential causality between the two was initially assessed by using negative emotions as exposure and AF as outcome. Subsequently, potential reverse causality was evaluated by using AF as exposure and negative emotions as outcome. The inverse variance weighted (IVW) method served as the primary analysis for the two-sample MR, supplemented by weighted median method, MR-Egger regression, Simple mode method, and Weighted mode method. Sensitivity analyses were performed using the MR pleiotropy residual sum and outlier test (MR-PRESSO), Cochran Q test, and leave-one-out analysis to ensure the robustness of the results. The two-sample MR analyses revealed that genetic susceptibility to AF had no potential causal effect on negative emotions (p > 0.05). Conversely, genetic susceptibility to negative emotions was positively correlated with an increased relative risk of AF [odds ratio (OR), 1.173, 95% confidence interval (CI): 1.115-1.235, p = 8.475 × 10-10]. Furthermore, neither horizontal pleiotropy nor heterogeneity was detected in the analysis. Genetic evidence from the study supports a potential causal link between negative emotions and AF. The study suggests that negative emotions may elevate the risk of AF, and the escalation of negative emotions in AF patients is more likely attributable to modifiable factors rather than genetically related factors.

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.

Association Between Arterial Stiffness Index and Age-Related Diseases: A Mendelian Randomization Study.

Arterial stiffness is an emerging indicator of cardiovascular risk, but its causal relationship with a variety of age-related diseases is unclear. The objective is to assess the causal relationship between arterial stiffness index (ASI) and age-related diseases by Mendelian randomization (MR) analysis. We obtained instrumental variables associated with age-related diseases from genome-wide association studies (GWAS) of 484,598 European individuals, and data for ASI were obtained from the UK Biobank GWAS of 127,127 participants. We used the inverse variance-weighted as the primary analysis method. In addition, several sensitivity analyses including MR-Egger, weighted-median (WM), Mendelian randomization pleiotropy residual sum and outlier, and Cochran's Q test were performed to test the robustness of the results. Reverse MR analysis was also performed to assess reverse causal relationships between age-related diseases and ASI. We verified the causal relationship between eight age-related diseases and ASI, of which cardiovascular disease (β = 0.19), gallbladder disease (β = 0.85), liver, biliary, or pancreas problem (β = 1.02), hypertension (β = 0.19), joint disorder (β = 0.53), and esophageal disorder (β = 2.10) elevated ASI. In contrast, hyperthyroidism or thyrotoxicosis (β = -2.17) and bowel problems (β = -1.83) may reduce ASI. This MR analysis reveals causal relationships between ASI and several age-related diseases. ASI is expected to be a potential indicator of health conditions for older populations.

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.

Cathepsins and neurological diseases: a Mendelian randomization study.

The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases. This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis. We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases. Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.