Myocarditis is closely linked to immune dysregulation, yet the causal roles of circulating inflammatory proteins in its development remain incompletely understood. This study aimed to explore whether specific inflammatory proteins are causally associated with myocarditis and to assess their potential translational relevance. We applied a two-sample Mendelian randomization (MR) using genome-wide association studies (GWAS) summary statistics for 91 circulating inflammatory proteins and myocarditis to identify causal associations. Candidate targets were refined through differential gene expression analysis of GEO datasets, followed by enrichment and protein-protein interaction (PPI) analyses. Cell-type-specific expression was confirmed using single-cell RNA sequencing (scRNA-seq) of myocarditis tissue. Drug prediction and molecular docking analyses were performed for the key target. MR identified interleukin-10 receptor subunit beta (IL10RB) and leukemia inhibitory factor (LIF) as potential causal proteins for myocarditis. LIF was prioritized as a key candidate target via transcriptomics, enrichment, and PPI analysis. scRNA-seq showed high LIF expression in dendritic cells, mural cells, and fibroblasts. Drug prediction and docking evaluated its therapeutic potential. Elevated circulating LIF levels may be causally linked to increased myocarditis risk, supporting its potential as both a predictive biomarker and a therapeutic target. These results provide a rationale for further experimental studies to clarify the context-dependent roles of LIF in myocardial inflammation and to evaluate LIF-directed interventions.

Scar formation following significant tissue injury remains a major clinical challenge, with metabolic processes and inflammation critically influencing tissue remodeling and fibrotic outcomes. This study aims to elucidate the causal relationships between plasma metabolites and scar pathogenesis using Mendelian randomization (MR). By employing a two-sample MR approach, we analyzed genetic variants from GWAS as instrumental variables (IVs) to assess the impact of plasma metabolites on scar formation. Data on metabolite levels were sourced from a GWAS database of 8299 individuals, and scar outcome data involved 463,010 European skin tissue samples. Five MR methods were utilized to ensure robust causal inference, including inverse variance weighting, MR-Egger regression, and weighted median, complemented by sensitivity analyses to address potential confounding factors and pleiotropy. The analysis of MR identified a total of four metabolites significantly associated with scar risk. Among them, (S)-α-amino-ω-caprolactam, N-acetylalanine and glycochenodeoxycholate 3-sulfate were linked to increased scar formation, while alliin demonstrated protective effects. Consistency across different MR methods underscored the robustness of these findings. Sensitivity analyses confirmed the absence of pleiotropy and the stability of causal estimates. The identified causal relationships between specific plasma metabolites and scar formation suggest that metabolic modulation may offer new therapeutic avenues for managing scar development.

Plasma proteins are potential biomarkers and drug targets that offer insights into the biological underpinnings of depression; yet, evidence linking them to depression is scarce. To identify depression-linked proteins, we conducted differential protein abundance analysis (DPAA) on 2920 plasma proteins among 48,378 UK Biobank participants. Among DPAA-identified proteins, we conducted network and enrichment analyses to reveal possible biological mechanisms, and Mendelian randomization (MR) to explore causal links with depression using summary GWAS data for proteins (N=34,557) and depression (166,773 cases, 507,679 controls). The druggability assessment was also done to identify potential drug targets. Through DPAA, we identified 22 proteins associated with depression (Padjusted<1.71×10-5), with each SD in protein levels corresponding to an 11%-27% difference in depression risk. Most proteins were positively associated, whereas LRRN1, CNTN5, and ADAMTS8 showed inverse relationships. These proteins were enriched in carbohydrate binding, PI3K/AKT and NF-κB signalling, and cytokine-receptor interactions. Although MR suggested causal evidence for BTN3A2(Padjusted<2.27×10-3), colocalization indicated likely confounding by linkage disequilibrium (PPH3 =73.5%). Other proteins (LGALS4, ADAMTS8, TNFRSF10B, CXADR, IGFBP4, and PRSS8) showed weak causal associations (P<0.05) with little colocalization support (PPH4≤6.3 %). ADAMTS8 and TNFRSF10B were not replicated in non-Europeans. Many of these proteins were known druggable targets in diverse diseases. Several plasma proteins were associated with depression and enriched in immune-inflammatory pathways, though causal evidence was limited. Their druggability underscores the repurposing opportunities for immune dysregulations related to depression.

Exploring estrogen synthesis and metabolism related markers and immune dynamics in osteoporosis-insights from single-cell RNA sequencing and Mendelian randomization.

Fufang Banmao Capsule (FBC) is clinically applied in the treatment of non-small cell lung cancer (NSCLC), yet its underlying pharmacological mechanism remains to be fully elucidated. This study aimed to systematically elucidate the pharmacological actions of FBC against NSCLC by integrating network pharmacology and Mendelian randomization approaches. Active components and potential targets of FBC were retrieved from the BATMAN-TCM database, while NSCLC-related therapeutic targets were collected from OMIM, TTD, and DisGeNet. Enrichment analysis and a "Herbs-Ingredients-Targets-Pathways" network were constructed. Core targets were further identified through protein-protein interaction and Mendelian randomization analyses, followed by colocaliza tion tests and molecular docking validation. A total of 152 potential FBC targets for NSCLC were identified, with seven candidates shortlisted. Among these, TNF and PIK3CA emerged as key protective targets (P<0.0025, OR<1). Colocalization analysis suggested possible shared genetic causality of TNF and PIK3CA single nucleotide polymorphisms with increased NSCLC risk. Molecular docking confirmed strong binding interactions between these targets and active FBC compounds such as resveratrol. The findings provide a theoretical foundation and new research directions for further investigation into the anti-NSCLC mechanism of FBC, supporting future innovation in therapeutic strategies.

SELE is associated with reduced breast cancer susceptibility: Evidence from Mendelian randomization and single-cell transcriptome.

Transcriptomic integration nominates FOXN2 as a candidate schizophrenia risk gene.

Genetic evidence from proteome-wide analysis identifies plasma proteins driving risk of respiratory tract infections.

Psychosis is a clinically heterogenous disorder associated with significant difficulties with social and occupational function (psychosocial disability; PD). While environmental and cognitive factors are identified predictors of PD, the genetic contribution remains unclear. Here, we investigated the hypothesis that objective social participation (SP) and occupational engagement are genetically influenced. We performed mixed-linear-model genome-wide association studies of these phenotypes in the UK Biobank (N∼404,500) and a series of post-hoc analyses including Mendelian randomization (MR) to interpret findings. SP was defined as the frequency of social visits and leisure activities based on response to questionnaires. Occupational engagement was represented by two variables: occupational function (OF) and the established Not in Education, Employment, and Training (NEET) measure, both derived from employment status responses. We identified 17 independent loci for SP, with a SNP-based heritability of 4.1%. A list of contributory genes included TNRC6B, STAU1, CDH7, GBE1, DDX27, and several known schizophrenia risk genes including CSE1L, ZNF536 and TCF4. The regulation of synaptic signalling was implicated in the biology of SP by gene-set analysis. SNP-based heritabilities for OF and NEET were 1.8% and 1.3% respectively and DRD2 was associated with both phenotypes by gene-based analysis. Reduced SP and occupational engagement demonstrated genetic correlations with an increased risk for neuropsychiatric disorders, socioeconomic deprivation, lower cognitive ability, loneliness, neuroticism and chronic pain. MR indicated that attention-deficit hyperactivity disorder and schizophrenia were likely causal for reduced occupational engagement. PD has a genetic component with shared genetic links and relationships with neuropsychiatric disorders and related traits.

Prenatal exposure to antiseizure medications and risk of autism spectrum disorder in offspring: an integrated pharmacovigilance and two-sample mendelian randomization study.

Decoding metabolic reprogramming heterogeneity across bladder cancer stages using single-cell and spatial multi-omics approaches.

Cell-type-specific genetic architecture of postpartum depression: A single-cell Mendelian randomization framework for causal gene discovery.

Single-cell transcriptomic mendelian randomization and co-localization reveal immune-mediated regulatory mechanisms and drug targets in atopic dermatitis.

Unraveling the neural underpinnings of major depressive disorder and pain: A mendelian randomization study and mediation analysis.

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global adult population, is a metabolic-associated hepatic disorder characterized by the interplay between inflammation and metabolism. Although evidence linking inflammatory factors and plasma metabolites to NAFLD progression, their causal relationships and mediating mechanisms remain unclear. This study employed a bidirectional Mendelian randomization (MR) approach combined with mediation analysis to investigate the causal relationships between inflammatory factors, plasma metabolites, and NAFLD. Summary data for 91 inflammatory factors and 1400 plasma metabolites were extracted from the genome-wide association studies databases and analyzed using MR. Mediation analysis was performed to examine whether the nine selected metabolites mediated the relationship between the eight inflammatory factors and NAFLD. All the analyses included tests for heterogeneity and pleiotropy. This study identified 11 inflammatory factors and 110 plasma metabolites that were significantly associated with NAFLD. Mediation analysis revealed that specific metabolites, including pregnenetriol disulfate, alanine: asparagine ratio, and X-21471, mediate the relationship between inflammatory factors and NAFLD. Notably, X-21471 was identified as a shared mediator of both tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CCL20. This integrative MR mediation analysis delineates an inflammation-metabolism-NAFLD axis, in which specific metabolites (X-21471, pregnenetriol disulfate) transmit pro-inflammatory signals (TNFRSF9/CCL20) involved in NAFLD pathogenesis. These findings suggest that combined targeting of TNFRSF9 and X-21471 may represent a precise preventive strategy for high-risk populations with metabolic comorbidities.

m6A-metabolite axes in depression: METTL14 network dysregulation and RBM15 lipid protection.

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is linked to worse outcomes in respiratory viral infections, especially COVID-19. Understanding genetic and mechanistic connections may improve risk assessment and treatment strategies. Aim: To investigate the genetic and biological links between COPD and respiratory viral infections. Materials and Methods: Using three COVID-19 outcomesSARS-CoV-2 infection, COVID-19 hospitalisation, and critical COVID-19 as representative cases. In parallel, we conducted literature-based functional pathway analysis to identify and map shared molecular, cellular, and tissue/organ-level mechanisms linking COPD to both COVID-19 and viral infections more broadly, enabling visualisation of biologically plausible pathways contributing to disease susceptibility and severity. Results: Our Mendelian Randomisation (MR) analysis revealed a genetic predisposition in individuals with COPD to an increased risk of severe COVID-19 {Odds Ratio (OR)=1.16, 95% CI: 1.01–1.34, p=0.033}, while no reverse causal effect of COVID19 on COPD was observed (p&gt;0.37). Functional pathway analysis highlighted key overlapping molecular players- such as Transmembrane Serine Protease (TMPRSS2), AngiotensinConverting Enzyme 2 (ACE2), Tumour Necrosis Factor (TNF), Interleukin (IL)-6, Interferons (IFNs), Dipeptidyl Peptidase-4 (DPP4) and Human Leukocyte Antigen (HLA) alleles- and dysregulated biological processes, including inflammation, oxidative stress, apoptosis, coagulation, angiogenesis, and immune responses. These findings support a model where SARS-CoV-2 infection exacerbates pre-existing pathological pathways in COPD, contributing to more severe disease outcomes. Conclusion: This study provides genetic and mechanistic evidence supporting the heightened vulnerability of COPD patients to severe COVID-19 and general viral infections. The identified shared molecular pathways may inform future therapeutic targets and guide clinical risk stratification in chronic respiratory disease management.

Modified Xuan-Bi-Qing-Ying decoction alleviates septic liver injury by regulating autophagy and apoptosis via HIF-1α signaling pathway.

Causal role of 46 pathogen-derived antibodies in prostate disease insights from two-sample and Bayesian-weighted Mendelian randomization.

Epidemiologic studies suggest that patients with Parkinson disease (PD) may have lower levels of vitamin B12 compared with healthy controls, and it was proposed that patients with PD could benefit from vitamin B12 supplementation. Functional studies have shown that B12 could modify LRRK2 activity and may directly interact with alpha-synuclein. The aim of this study was to investigate the role of common and rare variants in genes related to B12 metabolism and assess the potential causal relationships between B12 levels and PD risk, age at onset, and motor/cognitive progression. We investigated the association between common and rare variants in genes involved in vitamin B12 metabolism. Rare variants (minor allele frequency <0.01) were analyzed using the optimal sequence kernel association test in 4,815 patients with PD and 65,607 controls from 2 independent cohorts. We constructed pathway-specific polygenic risk scores (PRSs) for genes essential to B12 metabolism and for genes identified in previous genome-wide association studies (GWASs) on B12 metabolism. Mendelian randomization and genetic correlation analyses were applied to explore the relationship between vitamin B12 levels and PD risk, age at onset, and disease progression. Our analysis showed no associations between common variants of genes crucial in B12 metabolism and PD. Pathway PRSs identified nominal association between B12-related genes and PD (odds ratio [OR] = 1.061, 95% CI 1.004-1.121, p = 0.038), which did not survive Bonferroni correction. In the rare-variant analysis, we identified a significant association between variants with high Combined Annotation Dependent Depletion scores in the CUBN gene (p = 6.07E-05; Pfdr = 0.005) in the Accelerating Medicines Partnership-PD cohort, driven by the benign variant p.G3114S (OR = 3.3; p = 3.56E-05); however, this was not validated in the meta-analysis. We did not identify a potentially causal relationship between vitamin B12 levels and the risk, age at onset, or progression of PD. In addition, no genetic correlation was observed between vitamin B12 and PD risk or age-at-onset GWASs. Overall, our analyses indicate lack of genetic link between B12 levels or metabolism and PD.