MR-Egger Methods Research Articles

Dietary habit and risk of rheumatoid arthritis: a mendelian randomization study identifying protective and risk factors.

Dietary habit significantly contributes to the initiation and progression of rheumatoid arthritis (RA). Dietary choices intersect with a range of clinical and societal factors. The utilization of cross-sectional methodologies in numerous studies poses a challenge in establishing definitive causality for the noted associations. Moreover, within identical food categories, specific items may elicit diverse effects on the pathogenesis of RA, and the correlation between several prevalent food items or beverages and RA remains inadequately explored. We performed a two-sample Mendelian Randomization (MR) study to evaluate the causal impact of 27 distinct dietary habits and RA susceptibility. These dietary-related phenotypes encompass both the relative intake of the four macronutrients (fat, protein, carbohydrates, and sugar) and 23 specific single food intake. Several filtering steps were employed to select eligible genetic instruments strongly associated with each of the traits. The random-effects inverse-variance weighted, weighted median, and MR-Egger methods were employed for MR estimations. Sensitivity analyses and power calculations were executed to ensure the robustness of our study. After rigorous single-nucleotide polymorphism (SNP) filtering procedures, 611 SNPs were included in our ongoing investigations. The consumption of dried fruit, bread, and alcohol emerged as protective factors, while beef, processed meat, and coffee intake were identified as risk factors. The robustness of our study was confirmed through the outcomes of sensitivity analysis and power calculation. The ongoing investigations furnish evidence that accentuates the influence of diet on RA disease activity, underscoring the importance of delineating the optimal nutritional lifestyle for RA patients.

Causal association between allergic diseases and celiac disease: a bidirectional two-sample and multivariable Mendelian-randomization study

Objective This study aimed to assess the causality of allergic diseases and celiac disease. Methods We collected summary-level data from publicly available genome-wide association studies to conduct our bidirectional two-sample and multivariable Mendelian randomization analysis. Furthermore, a series of sensitivity analyses were applied to validate our findings. Results In bidirectional two-sample MR analyses, we found a significant causal effect of atopic dermatitis (AD) on CD (Inverse-variance weighted (IVW): odds ratio [OR] = 1.302, 95% confidence interval [CI] = 1.152-1.471, P < 0.001). We also found a significant causal effect of allergic rhinitis (AR) on CD (IVW: OR = 4.181, 95% CI = 1.495-11.697, P = 0.006). However, the MR-Egger method indicated a different causal effect direction compared to the IVW and weighted median method. After Bonferroni correction, the result of asthma on CD is suggestive of a causal effect (IVW: OR = 1.186, 95% CI = 1.021-1.378, P = 0.026). No causal effects were found when CD was considered as an exposure variable. In MVMR analyses, after separately and jointly adjusting for the influence of smoking and BMI, the causal effect of AD on CD remained robust. Conclusions Our study suggests that AD is a risk factor for CD and it is considered suggestive of a causal relationship between asthma and CD. Further research is needed to explore the potential mechanisms underlying this causal effect.

Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study.

Reproductive endocrine disorders (RED), including polycystic ovary syndrome (PCOS), endometriosis (EMs), and female infertility (FI), significantly affect women's health globally, with varying prevalence across different regions. These conditions can be addressed through medication, surgical interventions, and lifestyle modifications. However, the limited understanding of RED's etiology and the substantial economic burden of its treatment highlight the importance of investigating its pathogenesis. Metabolites play a critical role in metabolic processes and are potentially linked to the development of RED. Despite existing studies suggesting correlations between metabolites and RED, conclusive evidence remains scarce, primarily due to the observational nature of these studies, which are prone to confounding factors. This study utilized Mendelian Randomization (MR) to explore the causal relationship between metabolites and RED, leveraging genetic variants associated with metabolite levels as instrumental variables to minimize confounding and reverse causality. Data were obtained from the Metabolomics GWAS Server and the IEU OpenGWAS project. Instrumental variables were selected based on their association with the human gut microbiota composition, and the GWAS summary statistics for metabolites, PCOS, EMs, and FI were analyzed. The MR-Egger regression and random-effects inverse-variance weighted (IVW) methods were employed to validate the causal relationship. Cochran's Q test was employed to evaluate heterogeneity, sensitivity analysis was performed using leave-one-out analysis, and for pleiotropy analysis, the intercept term of MR-Egger's method was investigated. The MR analysis revealed significant associations between various metabolites and RED conditions. For instance, a positive association was found between 1-palmitoylglycerophosphocholine and PCOS, while a negative association was noted between phenylacetate and FI. The study identified several metabolites associated with an increased risk and others with protective effects against PCOS, EMs, and FI. These findings highlight the complex interplay between metabolites and RED, suggesting potential pathways through which these conditions could be influenced or treated. This MR study provides valuable insights into the causal relationship between metabolites and female reproductive endocrine disorders, suggesting that metabolic alterations play a significant role in the pathogenesis of PCOS, EMs, and FI, and offering a foundation for future research and therapeutic development.

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.

Causal role of immune cells in muscle atrophy: mendelian randomization study

Immune system and inflammation had a great influence on the progression of muscle atrophy. However, the causal relationship with specific immune cell traits remained uncertain. The aim of this study was to elucidate the genetic influences on these associations, providing insights into the underlying mechanisms of muscle atrophy. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between immune cell phenotypes and muscle atrophy. Data on immune cell phenotypes were obtained from a research cohort containing data on 731 immune cell phenotypes and data on muscle atrophy were sourced from a Finnish database. MR analysis was performed using the MR-Egger method, weighted median, inverse variance weighting, heterogeneity testing, sensitivity analysis, and multiplicity analysis, with results subjected to false discovery rate(FDR) correction. Additionally, the UK Biobank cohort was utilized as an external validation. A total of 31 immune phenotypes with causal relationships with muscle atrophy were identified, including various phenotypes of conventional dendritic cells, myeloid cells, T cells/B cells/natural killer cells, regulatory cells, and T cell maturation stages. Among them, 12 immune phenotypes were identified as exhibiting a positive causal relationship with muscle atrophy, while 19 immune phenotypes were demonstrated to have a negative causal association, highlighting the complex interactions between immune cells and muscle health. The results of the reverse MR analysis indicated that a negative correlation between muscle atrophy and CD28 on secreting Treg (OR = 0.9038, 95%CI:0.8308 ~ 0.9832, P = 0.0186). A significant positive correlation was revealed by external datasets between the CD25 on IgD + CD38- immune phenotype and the risk of muscle atrophy, which was consistent with the trend observed in the training group (OR = 1.1041, 95% CI: 1.1005–1.1076, P = 0.0263). No evidence of pleiotropy was observed, and the reliability of these findings was demonstrated by the leave-one-out analysis. The findings highlight significant correlations between certain immune cell features and muscle atrophy, providing potential targets for further investigation of immunological mechanisms and therapeutic interventions for this condition.

Role of double-negative autoreactive cells (CD4−CD8−) in phosphatidylcholine-mediated rheumatoid arthritis: A Mendelian randomization study

ObjectiveMendelian randomization (MR) was employed to explore the potential causal relationship between liposomes (LP) and rheumatoid arthritis (RA), with a focus on the mediating roles of immune cells (IC). MethodsBy screening public GWAS data, LP were used as exposure data, RA as outcome data, and IC as mediating factors. The Inverse Variance Weighted (IVW) method was the main analytical technique used in this paper to evaluate causal effects. Additional techniques included the MR-Egger, weighted median, weighted mode, and simple mode methods. Cochran's Q and MR-Egger were utilized for heterogeneity and multi-effect analysis. ResultsPhosphatidylcholine was revealed to enhance the risk of RA by MR analysis (P = 0.013, OR = 1.073, 95%CI = 1.015–1.136). There was no strong evidence that RA could affect liposome changes (IVW: P = 0.705, OR = 0.992, 95%CI = 0.952–1.034). The IVW method showed that increased levels of phosphatidylcholine were notably linked to higher levels of Double-Negative Autoreactive Cells (CD4−CD8−, DNAC) (P = 0.006, OR = 1.152, 95%CI = 1.041–1.276). The IVW approach showed that increased levels of DNAC were substantially linked to a higher risk of RA (P = 0.001, OR = 1.105, 95%CI = 1.041–1.173). Of the genetically predicted liposomes mediated by DNAC, 19.2 % were found. ConclusionThe present work established a causal association between LP and RA, and identified a potential mediating influence of IC. However, the specific mechanism of LP triacyl-glycerol and IC on RA is still unclear, and further research is needed.

Genetically predicted plasma metabolites mediate the causal relationship between gut microbiota and primary immune thrombocytopenia (ITP).

Primary immune thrombocytopenia (ITP) is an immune-mediated hematologic disorder characterized by a reduction in platelet count, increasing the risk of bleeding. Recent studies have indicated a close association between alterations in gut microbiota and the development of ITP. However, the mechanisms by which gut microbiota influence the occurrence and progression of ITP through plasma metabolites remain poorly understood. Evidence suggests extensive interactions between gut microbiota and plasma metabolites, implying a potential role for gut microbiota in influencing ITP through alterations in plasma metabolites, which requires further investigation. In this study, summarized GWAS data (including 211 gut microbiota taxa, 1,400 plasma metabolites or ratios, and an ITP patient cohort) were retrieved from the MiBioGen and GWAS Catalog databases. Using a two-sample Mendelian randomization (MR) approach, we screened gut microbiota and plasma metabolites potentially causally related to ITP. We further identified plasma metabolites serving as mediators through which gut microbiota affect ITP and calculated the strength of the mediation effect. To ensure result stability, we primarily used the inverse variance weighted (IVW) method as the main judgment index. We also utilized MR Egger and inverse variance weighted methods to detect heterogeneity in the results, and employed MR-Egger and MR-PRESSO methods to assess the presence of pleiotropy. Though two-sample MR analysis, 8 gut microbiota taxa were found to have causal relationships with ITP. After excluding six plasma metabolites with pleiotropy, 39 plasma metabolites were found to be causally related to ITP (P < 0.05). Eleven plasma metabolites were identified as having causal relationships between gut microbiota and plasma metabolites. Finally, using the delta method, it was calculated that Sphingomyelin levels (8.0%, 95%CI: 0.9% to 11.5%, P = 0.047) and Glucose-to-mannose ratio (6.5%, 95%CI: 0.7% to 9.5%, P = 0.039) are intermediates for Intestinimonas influencing ITP, while Bilirubin (Z,Z) to etiocholanolone glucuronide ratio (5.6%, 95%CI: 4.7% to 6.9%, P = 0.043) is an intermediate for Senegalimassilia influencing ITP. Gut microbiota can influence the development of ITP through changes in plasma metabolites. Sphingomyelin levels, Glucose-to-mannose ratio, and Bilirubin (Z,Z) to etiocholanolone glucuronide ratio are newly discovered intermediates through which gut microbiota influence ITP, providing potential indicators and targets for clinical diagnosis and treatment. This study highlights the intricate relationship between gut microbiota and plasma metabolites in the context of ITP, suggesting new avenues for clinical diagnosis and treatment.

Leisure screen time and diabetic retinopathy risk: A Mendelian randomization study.

The aim of this study was to investigate whether leisure screen time (LST) increases the risk of diabetic retinopathy (DR) using the Mendelian randomization (MR). This study employed a two-sample MR analysis, utilizing 63 single-nucleotide polymorphisms as instrumental variables (IVs) to assess the causal relationship between LST and the risk of Dr. To ensure the robustness of the results, a multi-effect test was conducted to evaluate the validity of the IVs. Additionally, heterogeneity tests were performed to explore differences among sub-samples. Sensitivity analyses were also conducted to further validate our findings. The impact of LST on the risk of DR was observed in both inverse variance weighted (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.04-1.43, P = 1.38 × 10-2) and weighted median (OR: 1.30, 95% CI: 1.05-1.61, P = 1.46 × 10-2) analyses. However, the MR-Egger method (OR: 0.66, 95% CI: 0.32-1.36, P = .273) did not find an increased risk of DR with increased LST. The pleiotropy test yielded a P-value of P = .09. Heterogeneity tests showed that the Q value for the inverse variance weighted method was 71.39 with a P-value of 0.17, indicating no significant heterogeneity. These results suggest that the IVs might be appropriate, and the analysis results could be robust. A large-scale MR analysis suggests a causal relationship between LST and the risk of Dr.

Cysteine cathepsins and autoimmune diseases: A bidirectional Mendelian randomization.

Cysteine cathepsins are proteolytic enzymes crucial in various physiological and pathological processes, primarily operating within lysosomes. Their functions include protein degradation, immune system regulation, and involvement in various diseases. While some cysteine cathepsins play important roles in the immune system, their connection to autoimmune diseases remains unclear. This study proposes using Mendelian randomization to explore the causal relationship between cysteine cathepsins and autoimmune diseases. Single nucleotide polymorphisms (SNPs) for cysteine cathepsins were obtained from a publicly available genome-wide association study (GWAS) dataset, while outcome SNP data were sourced from 10 separate GWAS datasets. Mendelian randomization (MR) analysis employed the Wald ratio (WR) and inverse variance weighted (IVW) approach as primary methods, supplemented by the weighted median and MR-Egger methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analysis was conducted using the MR-PRESSO method. The association strength between exposure and outcome was evaluated using odds ratios (OR) with 95% confidence intervals (CI). The study identified a potential positive correlation between elevated cathepsin B and psoriasis (Wald ratio OR = 1.449, 95% CI: 1.053-1.993, P = .0227). Elevated cathepsin F was potentially linked to ulcerative colitis (WR OR = 1.073, 95% CI: 1.021-1.127, P = .0056), ankylosing spondylitis (WR OR = 1.258, 95% CI: 1.082-1.463, P = .0029), and primary biliary cholangitis(PBC) (WR OR = 1.958, 95% CI: 1.326-2.889, P = .0007). Conversely, cathepsin H appeared protective against celiac disease (WR OR = 0.881, 95% CI: 0.838-0.926, P = 6.5e-7), though elevated levels may increase the risk of type 1 diabetes (IVW OR = 1.121, 95% CI: 1.053-1.194, P = .0003) and PBC (WR OR = 1.792, 95% CI: 1.062-3.024, P = .0288). Cathepsin Z was also associated with an increased risk of type 1 diabetes (IVW OR = 1.090, 95% CI: 1.006-1.181, P = .0349). The MR analysis suggests potential risks of cathepsin B with psoriasis, cathepsin F with ulcerative colitis, ankylosing spondylitis, and PBC, and cathepsin Z with type 1 diabetes. Conversely, cathepsin H may protect against celiac disease but could increase the risk of type 1 diabetes and PBC.

Bidirectional causal relationship between glucose-lipid metabolism, obesity indicators, and myocardial infarction: a bidirectional Mendelian randomization analysis study

Objective: To explore the causal association of glucose-lipid metabolism and obesity indicators with myocardial infarction by a two-sample Mendelian randomization analysis. Methods: Single nucleotide polymorphisms (SNPs) related to phenotypes were obtained from genome-wide association study databases. The body mass index (BMI) and glycated hemoglobin dataset includes 99 998 samples and 8 126 035 SNPs; the waist-to-hip ratio dataset includes 224 459 samples and 2 562 516 SNPs; the waist circumference and hip circumference dataset includes 462 166 samples and 9 851 867 SNPs; the fasting glucose dataset includes approximately 12 million SNPs; the low-density lipoprotein cholesterol (LDL-C) dataset includes 201 678 samples and 12 321 875 SNPs; the high-density lipoprotein cholesterol (HDL-C), and triglycerides dataset includes 156 109 samples and 15 784 414 SNPs; and the body fat percentage, whole-body fat mass, trunk fat percentage, and trunk fat mass dataset includes 454 588 samples and 9 851 867 SNPs. This study primarily used inverse-variance weighted method to analyze the associations between various exposure factors and outcomes. Heterogeneity among SNPs was assessed using Cochran's Q test, and horizontal pleiotropy of SNPs was examined using the MR-Egger method. Additionally, a multivariable MR approach was used to adjust for BMI, further validating associations between exposure factors and the risk of myocardial infarction. Results: Higher BMI (OR=1.070, 95%CI: 1.041-1.100), waist-to-hip ratio (OR=1.366, 95%CI: 1.113-1.677), LDL-C (OR=1.638, 95%CI: 1.488-1.803), triglycerides (OR=1.445, 95%CI: 1.300-1.606), waist circumference (OR=1.841, 95%CI: 1.650-2.055), hip circumference (OR=1.247, 95%CI: 1.132-1.372), body fat percentage (OR=1.795, 95%CI: 1.568-2.055), whole-body fat mass (OR=1.519, 95%CI: 1.381-1.670), trunk fat percentage (OR=1.538, 95%CI: 1.374-1.723), and trunk fat mass (OR=1.421, 95%CI: 1.294-1.561), as well as lower HDL-C (OR=0.799, 95%CI: 0.729-0.875), have causal effects on myocardial infarction (all P<0.05). After adjusting for BMI, hip circumference, trunk fat percentage, and trunk fat mass were no longer associated with myocardial infarction. However, waist-to-hip ratio (OR=1.457, 95%CI: 1.132-1.877), fasting glucose (OR=1.191, 95%CI: 1.024-1.383), glycated hemoglobin (OR=1.129, 95%CI: 1.034-1.233), LDL-C (OR=1.592, 95%CI: 1.314-1.929), triglycerides (OR=1.410, 95%CI: 1.279-1.553), waist circumference (OR=1.922, 95%CI: 1.448-2.551), body fat percentage (OR=1.421, 95%CI: 1.072-1.884), and whole-body fat mass (OR=1.295, 95%CI: 1.031-1.626) remained positively associated with myocardial infarction, while HDL-C (OR=0.809, 95%CI: 0.729-0.897) remained negatively associated. Conclusions: Abdominal obesity and dysregulation of glucose-lipid metabolism are risk factors for myocardial infarction. Screening for glucose-lipid metabolism (fasting glucose, HDL-C, LDL-C, triglycerides) and obesity-related indicators (waist circumference, waist-to-hip ratio, body fat percentage, and whole-body fat mass) is of great importance for the primary prevention of myocardial infarction.

Identification of immune traits associated with neurodevelopmental disorders by two-sample Mendelian randomization analysis

BackgroundOne of the main causes of health-related issues in children is neurodevelopmental disorders (NDDs), which include attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourette syndrome (TS). Nonetheless, there is relatively little prior research looking at the link between immunological inflammation and NDDs. Our work uses a two-sample Mendelian Randomization (MR) approach to provide a thorough evaluation of the causal effects of immune traits on ADHD, ASD, and TS.MethodsAs exposures, 731 immunological traits’ genetic associations were chosen, and the outcomes were genome-wide association data for ADHD, ASD, and TS. The inverse-variance weighted (IVW), weighted median (WM), and MR-Egger methods were used to conduct MR analysis. The results’ robustness, heterogeneity, and horizontal pleiotropy were confirmed using extensive sensitivity analysis.ResultsWith single-nucleotide polymorphisms serving as instruments and false discovery rate (FDR) correction applied, the study found that significantly higher expression of CD62L on CD62L+ myeloid DC (IVW, OR: 0.926, 95% CI 0.896~0.958, P = 9.42 × 10–6, FDR = 0.007) and suggestively higher absolute cell count (AC) of CD28 + DN (CD4-CD8-) (IVW, OR: 0.852, 95% CI = 0.780 ∼ 0.932, P-value = 4.65 × 10−4, FDR = 0.170) was associated with a lower risk of ADHD. There was no pleiotropy, and the causal relationships were strong according to sensitivity, leave-one-out, and MR-Steiger directionality tests. For ASD and TS, no harmful or protective immune traits were observed.ConclusionsThe results of the study lend credence to the theory that deficiency in CD62L on CD62L+ myeloid DC and CD28 + DN (CD4-CD8) AC may contribute to the onset of ADHD.

Causal relationship between circulating inflammatory proteins and risk of different types of encephalitis: A two-sample Mendelian randomization study

BackgroundCytokines are potent molecules of the immune response. They act at the site of inflammation and circulate in the bloodstream. However, there are few studies on encephalitis and circulating inflammatory proteins. MethodsIn this study, Mendelian randomization (MR) was used to explore the potential causal effect of 91 circulating inflammatory proteins on 3 different types of encephalitis. Causal effects were examined using Steiger, MR-Egger, weighted median, and inverse variance weighting (IVW) methods. IVW methods were primarily used for results interpretation. In addition, sensitivity analyses were performed, including assessment of heterogeneity, horizontal pleiotropy, and Leave-one-out techniques. ResultsWe subjected 91 circulating inflammatory proteins to MR analysis of causality with each of the three types of encephalitis. The results suggested that the inflammatory factors with a potential causal relationship with viral encephalitis were caspase 8, C-X-C motif chemokine 6, interleukin-10, interleukin-15 receptor subunit alpha, interleukin-7, and TNF-beta. Inflammatory factors potentially causally associated with acute disseminated encephalomyelitis are beta-nerve growth factor, cystatin D, interleukin-7,Latency-associated peptide transforming growth factor beta 1,and neurotrophin-3.Inflammatory factors potentially causally associated with autoimmune encephalitis are C–C motif chemokine 25, hepatocyte growth factor, latency-associated peptide transforming growth factor beta 1, programmed cell death 1 ligand 1, sulfotransferase 1A1, and tumor necrosis factor. ConclusionThis finding identifies potential causal effects of certain circulating inflammatory factors on susceptibility to three types of encephalitis. It also suggests the therapeutic potential of modulating the levels of these cytokines. A basis for further research is provided.

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.

Causal relationship between IgA nephropathy and common neuropsychiatric disorders: A two-sample Mendelian randomization analysis

ObjectiveUtilizing two-sample Mendelian randomization (TSMR), this study seeks to determine the causal relationship between IgA nephropathy and five prevalent neuropsychiatric disorders. By exploring the genetic associations between IgA nephropathy and neuropsychiatric disorders, this research aims to contribute to the prevention of neuropsychiatric disorders in patients with IgA nephropathy. MethodsPublic genome-wide association study databases were searched, with IgA nephropathy as the exposure factor, including 15,587 patients with IgA nephropathy and 462,197 healthy controls. The outcome factors were five common neuropsychiatric disorders (bipolar disorder, depressive disorder, schizophrenia, anorexia nervosa, and Alzheimer's disease), with outcome data drawn from five datasets in the PGC and GWAScatalog databases. Inverse-variance weighting served as the primary method for causal effect estimation, supplemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity was tested using Cochran's Q test, and sensitivity analysis was conducted using MR-Egger and MR-presso. ResultsMR analysis indicated a positive causal relationship between IgA nephropathy and depressive disorder (OR = 1.010, 95%CI: 1.003–1.017, P = 3.27 × 10−3), and a potential positive causal relationship between IgA nephropathy and anorexia nervosa (OR = 1.165, 95%CI: 1.030–1.319, P = 0.015). ConclusionThere is a positive causal relationship between IgA nephropathy and depressive disorder, and a potential positive causal relationship with anorexia nervosa. No causal relationship was found with schizophrenia, bipolar disorder, or Alzheimer's disease.

Identifying atheroprotective fruits and vegetables by Mendelian Randomization analysis.

Fruits and vegetables (FVs) are widely believed to mitigate the risk of atherosclerosis (AS). However, the causal relationships between specific FVs and AS risk factors remain unclear. This study performed two-sample Mendelian Randomization (MR) analysis to infer the causality of the intake of 28 kinds of FVs with AS, as well as its risk factors including blood low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and C-reactive protein (CRP). GWAS genetic data for these exposures and outcomes were extracted from the IEU open GWAS project. Heterogeneity was evaluated using both Inverse Variance Weighted (IVW) and MR-Egger methods. MR-Egger regression was specifically deployed to detect potential pleiotropy. Furthermore, a "leave-one-out" sensitivity analysis was conducted to determine the impact of each individual single nucleotide polymorphism (SNP) on the combined outcome. The analysis confirms a causal relationship between total fruit consumption and reduced levels of LDL-C (OR = 0.911, p = 0.007) and CRP (OR = 0.868, p = 0.008). Similarly, total vegetable intake is also causally associated with a reduction in CRP levels (OR = 0.858, p = 0.018). Specifically, garlic intake exhibits the most significant causal relationship with reduced risk of AS (OR = 0.985, p = 0.036) and also causally associated with lower levels of LDL-C and TG. Berry (OR = 0.929, p = 0.010) and potato (OR = 0.957, p = 0.020) intake both display a significant causal negative association with TG levels, while peach/nectarine consumption is significantly associated with reduced CRP levels (OR = 0.913, p = 0.010). This is the first MR study that systemically examined the causality between commonly consumed FVs and AS. Our findings highlight the atheroprotective effects of various FVs, particularly garlic, on cardiovascular health and the importance of tailored nutritional recommendations to prevent AS.

Assessing the causal relationship between CRP, IL-1α, IL-1β, and IL-6 levels and intervertebral disc degeneration: a two-sample Mendelian randomization study

Growing research has suggested an association between chronic inflammation and Intervertebral disc degeneration (IVDD), but whether there is a causal effect remains unknown. This study adopted two-sample Mendelian randomization (MR) approach to explore the etiological role of chronic inflammation in IVDD risk. Here, summary statistics for C-reactive protein (CRP), interleukin (IL)-1α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\alpha }$$\\end{document}, IL-1β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\beta }$$\\end{document}, IL-6 expression and IVDD were obtained from genome-wide association studies (GWAS) of European ancestry. MR analyses were conducted by using inverse variance weighted (IVW), Wald Ratio, weighted median, and MR-Egger method. Sensitivity analyses were conducted to assess the robustness of the results. The MR analyses suggested a lack of causal association of CRP, IL-6 , and IL-1α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\alpha }$$\\end{document} levels on IVDD (CRP-IVDD: odds ratio [OR] = 0.97, 95% confidence interval [CI] 0.86–1.09, P = 0.583; IL-6-IVDD: OR = 1.04, 95% CI 0.86–1.27, P = 0.679; IL-1α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\alpha }$$\\end{document}-IVDD: OR = 1.09, 95%CI 1.00–1.18, P = 0.058). However, there was a sign of a connection between genetically elevated IL-1β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\beta }$$\\end{document} levels and a decreased IVDD incidence (OR = 0.87, 95%CI 0.77–0.99, P = 0.03). Our findings suggest a connection between IL-1β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathcal {\\beta }$$\\end{document} levels and the risk of IVDD. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, the specific underlying mechanisms warrant further investigation.

Causal links between circulatory inflammatory cytokines and risk of digestive polyps: a Mendelian randomization analysis.

There is a high morbidity of polyps in the digestive tract, and certain subtypes of polyps are thought to induce cancer progression and often recur, which may be associated with chronic inflammation. Mendelian randomization (MR) can help identify potential causative relationships and inform early treatment action. We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and three types of polyps from European ancestry, respectively, including gastric polyp (6,155 cases vs. 341,871 controls), colonic polyp (22,049 cases vs. 332,368 controls) and gallbladder polyp (458 cases vs. 340,083 controls). Inverse-variance weighted (IVW), weight median (WM), and MR-Egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal circulatory cytokines with adjustment for pleiotropy effects. Our univariable MR using inverse-variance weight method identified causal associations of IL-2ra (OR: 0.892, 95%CI: 0.828-0.961, p = 0.003), MIG (OR: 1.124, 95%CI: 1.046-1.207, p = 0.001) and IL-18 (OR: 0.912, 95%CI: 0.852-0.977, p = 0.008) with gastric polyp, MIP1b (OR: 0.956, 95%CI: 0.927-0.987, p = 0.005) and IL-6 (OR: 0.931, 95%CI: 0.870-0.995, p = 0.035) with colonic polyp and IL-9 (OR: 0.523, 95%CI: 0.345-0.794, p = 0.0007) with gallbladder polyp. Finally, our MR-BMA analysis prioritized MIG (MIP = 0.332, MACE = 0.022; PP: 0.264, MSCE = 0.059), IL-18 (MIP = 0.302, MACE = -0.020; PP: 0.243, MSCE = -0.059) and IL-2ra (MIP: 0.129; MACE: -0.005; PP: 0.112, MSCE: -0.031) for gastric polyp, and MIP1b (MIP = 0.752, MACE = -0.033; PP: 0.665, MSCE = -0.044) and IL-6 (MIP: 0.196; MACE: -0.012; PP: 0.140, MSCE: -0.064) for colonic polyp, and IL-9 (MIP = 0.936, MACE = -0.446; PP: 0.781, MSCE = -0.478) for gallbladder polyp as the top-ranked protective factors. Our research advances the current understanding of the function of certain inflammatory biomarker pathways in the genesis and malignant mutation of polyps in the digestive tract. Deeper substantiation is necessary to assess the potential of these cytokines as pharmacological or lifestyle targets for digestive polyps prevention.

Effects of Iron, Copper, Zinc, and Magnesium on Chronic Widespread Pain: A Two-Sample Mendelian Randomization.

Background: Chronic widespread pain (CWP) affects approximately 10% of the adult population globally, causing significant physical and psychological distress. Micronutrients, such as iron, copper, zinc, and magnesium, are essential in various physiological functions, and their imbalances may impact pain perception and chronic pain conditions. Methods: This study used Mendelian randomization (MR) to investigate the causal relationships between micronutrient levels and CWP. Data were obtained from genome-wide association studies (GWASs) for iron, copper, zinc, and magnesium, and CWP data were sourced from large-scale GWASs with 461,857 European participants. Genetic variants were used as instrumental variables to infer causal relationships, minimizing confounding factors. Results: MR analysis revealed a significant association between higher iron levels and an increased risk of CWP (IVW, OR 1.01, 95% CI: 1.00-1.01, p = 0.029). This finding was supported by the weighted median and MR-Egger methods. No significant associations were found for copper, zinc, and magnesium levels. Conclusions: These results suggest that iron levels may influence pain perception and chronic pain conditions. Balanced iron levels are crucial for managing chronic pain. Regular monitoring and personalized treatment plans could benefit individuals with CWP. Further research is needed to understand the mechanisms linking micronutrient levels to chronic pain and to develop targeted therapeutic interventions.

Exploring the Influence of Cheese Consumption on Blood Metabolites: Implications for Disease Pathogenesis, with a Focus on Essential Hypertension

This study examines the causal effects of cheese consumption on blood metabolites and essential hypertension using Mendelian Randomization (MR). GWAS data from the Open GWAS project and FinnGen Biobank were analyzed, focusing on cheese intake, 249 metabolic traits, and hypertension. Instrumental variables were selected based on strict criteria, and causal relationships were assessed using IVW, weighted-median, and MR-Egger methods. Cheese consumption significantly influenced 118 metabolic traits, including amino acids, cholesterol esters, and triglycerides. Notably, it was linked to a reduction in hypertension risk (OR = 0.652, P < 0.0001). Mediation analysis identified 50 metabolic traits as intermediaries, accounting for 0.88% to 8.25% of the total effect. These findings suggest that moderate cheese intake may benefit cardiovascular health by lowering hypertension risk, emphasizing the importance of cheese type and dietary context in health recommendations.

Association of Physical Activity with Asthma and Chronic Obstructive Pulmonary Disease and Mediation of Frailty: Mendelian Randomization Analyses.

The existence of an association between physical activity (PA) and asthma and chronic obstructive pulmonary disease (COPD) has been confirmed in observational studies. Therefore, it is necessary to reveal whether there is a risk-effect relationship between physical activity and asthma and COPD through Mendelian randomization (MR) analysis. Univariate Mendelian randomization (UVMR) analyses were performed to examine the associations between moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA), accelerometer-assessed physical activity (AA), and strenuous exercise or other exercise (SSOE) with asthma and COPD. The methods of analysis were dominated by Inverse Variance-Weighted (IVW), Weighted median (WM), and MR-Egger methods. In addition, multivariate Mendelian randomization (MVMR) analyses were performed to correct the effects of four types of physical activity on asthma and COPD. Finally, potential mediating effect relationships were identified through mediation analyses. The results of Univariate Mendelian randomization analysis showed that SSOE could reduce the risk of asthma and COPD(asthma: OR=0.15,95% CI=0.04-0.58, P=0.006; COPD: OR=0.05, 95% CI=0.01-0.33, P=0.002). The results of the Multivariate Mendelian randomization analysis showed that SSOE was still able to reduce the risk of asthma and COPD after adjusting for the effects of different types of physical activity(asthma: 95% CI=-2.77--0.31, P=0.014; COPD: 95% CI=-4.00--0.50, P=0.012). Mediation analyses showed that frailty intervened in the causal relationship between physical activity and asthma and chronic obstructive pulmonary disease. SSOE is a protective factor for asthma and COPD in the European population, while frailty plays a mediating role.