Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the “microbiota” and “gut lymphocyte homing” hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828–0.986, P =  .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823–0.969, P =  .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013–1.157, P =  .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012–1.118, P =  .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835–0.986, P =  .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864–0.994, P =  .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630–0.833, P =  5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001–1.112, P =  .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.

Miscarriage represents a prevalent yet insufficiently studied adverse pregnancy outcome. The definitive causal links between various pathogens and miscarriage remain to be established. To investigate the causal connections between pathogen infections and miscarriage, we utilized a two-sample bidirectional Mendelian randomization (MR) analysis. We sourced genome-wide association studies data on pathogen infections from the UK Biobank, which included serological markers for infectious diseases and comprehensive whole-genome genetic information from approximately 10,000 individuals. Additionally, genome-wide association studies data on miscarriages were collected from 3 distinct European populations for our analysis. The MR analysis was primarily conducted using the inverse variance weighted method, complemented by Bayesian weighted MR and the weighted median method for robustness. To ensure the reliability of our findings, we performed heterogeneity and pleiotropy tests, leave-one-out sensitivity analyses, and a meta-analysis. Our extensive research has identified a causal association between miscarriage and infections by several human herpesviruses (HHV-1, HHV-3, HHV-4, HHV-6, and HHV-7), polyomaviruses (BK, JC, and Merkel cell polyomaviruses), and Chlamydia trachomatis (inverse variance weighted, P < .05). Notably, a meta-analysis of the integrated data highlighted the particularly high accuracy and consistency of the association with Merkel cell polyomavirus. Our MR analysis has clarified the causal relationships between specific pathogen infections and miscarriage, providing a critical foundation for the prevention and treatment of this adverse pregnancy outcome.

Gastric cancer (GC), as one of the most prevalent malignant tumors, significantly impacts individuals’ health. Many studies have examined the relationship between mitochondrial DNA (mtDNA) copy number and GC. However, conclusions remain inconclusive, with conflicting findings. The genome-wide association study summary statistics for mtDNA copy number were obtained from 2 sources: one from a robust cohort of 465,809 White individuals provided by the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the UK Biobank; and the other from a dataset comprising 395,718 UK Biobank participants. In addition, a total of 5 sets of genome-wide association study summary statistics for GC were obtained through datasets from Finland, the European Bioinformatics Institute, and the Integrative Epidemiology Unit at the University of Bristol, encompassing a total of 937,663 participants. Furthermore, we undertook a 2-sample bidirectional Mendelian randomization analysis to explore the association between mtDNA copy number and GC. The Inverse variance weighted (IVW) method was primarily utilized, complemented by 4 other validation methods. Based on our comprehensive investigation, no discernible causal relationship was found between mtDNA copy number and GC in both the training and validation cohorts (IVW, P > .05). Furthermore, in the reverse Mendelian randomization analysis, no association was observed between GC and mtDNA copy number either (IVW, P > .05). Additionally, all analyses showed no evidence of horizontal pleiotropy or heterogeneity. The findings of this study provide evidence that there is no causal relationship between mtDNA copy number and GC.

To date, evidence on the relationship between H. pylori infection and biliary diseases remains unclear. This Mendelian randomization (MR) study aim to investigate the causal relationship between H. pylori infection and various biliary system diseases. We obtained summary statistics for 7 hours. Pylori antibody levels and 5 biliary system diseases (cholelithiasis, cholecystitis, biliary system cancers, primary biliary cholangitis, and primary sclerosing cholangitis [PSC]) from public databases of different populations. The 2-sample bidirectional MR analysis was conducted using the Inverse-Variance Weighted (IVW) method, complemented by Bayesian Weighted MR. Heterogeneity analyses, tests for horizontal pleiotropy, and leave-one-out sensitivity analyses were performed to enhance the reliability and stability of the results. This study provided evidence for a causal relationship between H. pylori infection and cholelithiasis, biliary system cancers, and PSC (IVW, P < .05). However, no causal relationship was found between H. pylori infection and cholecystitis or primary biliary cholangitis (IVW, P > .05). Notably, the bidirectional MR analysis provided evidence of reciprocal causal relationships, with genetic liability to cholelithiasis, biliary tract cancer, and PSC likewise showing causal effects on H. pylori infection (IVW, P < .05). This study suggested a causal link between H. pylori infection and various biliary system diseases, discussing their intricate interplay. These findings are significant for advancing our understanding of H. pylori exposure and its role in the pathogenesis of biliary system diseases.

The pathophysiological mechanisms underlying diverticular disease (DD) remain incompletely understood, and there is considerable debate regarding the roles of gut microbiome features and inflammation-related proteins in the development of the disease. In this study, we employed mediation Mendelian randomization (MR) analysis to investigate the causal relationships among these 3 factors. In this study, we conducted a MR analysis on the genome-wide association studies data of 412 gut microbiome features (207 microbial taxa and 205 pathways), 91 inflammation-related proteins, and DD. We employed the inverse-variance weighted (IVW) method as our primary screening approach, followed by a mediation MR analysis to explore potential causal relationships among these 3 aspects. Our findings were further reinforced by comprehensive heterogeneity analyses, horizontal pleiotropy testing, outlier detection, and “leave-one-out” sensitivity analysis. Through our screening process, we identified potential causal relationships between DD and 18 gut microbiome features, as well as 6 inflammation-related proteins. These include s_Oscillibacter_unclassified (IVW odds ratio (OR): 1.139; 95% confidence interval (CI): 1.044–1.241, P = .003), g_Bilophila (IVW OR: 1.107, 95% CI: 1.016–1.206, P = .020), T-cell surface glycoprotein CD5 levels (IVW OR: 1.065, 95% CI: 1.011–1.123, P = .019), and inosine 5’-phosphate biosynthesis I (IVW OR: 0.882, 95% CI: 0.800–0.973, P = .012), etc. In the mediation MR analysis, we found that the genetic predictors of g_Bilophila and inosine 5’-phosphate biosynthesis I could explain 23.956% and 24.630% of the variation in T-cell surface glycoprotein CD5 levels, respectively. This study detailed analysis of the links between gut microbiome features, inflammation-related proteins, and DD offers key insights into DD pathogenesis and prevention.

Introduction: Celiac Disease (CeD) is a serious, lifelong autoimmune condition. There remains a significant unmet medical need for effective pharmacological treatments for CeD. Methods: We utilized summary statistics for 2,888 druggable genes from the eQTLGen Consortium and the FinnGen Consortium for CeD. In our Mendelian Randomization (MR) analysis, we identified genes associated with CeD that had a false discovery rate (FDR) < 0.05 using the Inverse Variance Weighted (IVW) method. To enhance the reliability of the results, we validated them through colocalization analysis and Summary-data-based Mendelian Randomization (SMR) analyses. Results: Through our analysis, we identified 18 druggable genes with a causal relationship to CeD under an FDR < 0.05. Subsequent colocalization and SMR analyses highlighted the PRKCD gene as a potential therapeutic target for CeD (IVW method: Odds Ratio 1.319, 95% Confidence Interval 1.182-1.471, P = 6.85E-07, FDR = 0.002). Additionally, these results have passed horizontal pleiotropy tests, heterogeneity analysis, and leave-one-out sensitivity analysis. Discussion: The identification of PRKCD as a therapeutic target represents a significant advancement in addressing the unmet medical need for CeD treatment. However, the hypothesis that PRKCD contributes to CeD pathogenesis by regulating tight junction proteins and altering intestinal barrier function requires further experimental validation in future studies. Conclusion: Our study is the first to identify the PRKCD gene as a potential therapeutic target for treating CeD, providing new insights into the treatment of CeD and guiding the development of corresponding therapeutic drugs.