Search Results (600)

We conducted a two-sample Mendelian randomization (MR) study including only European men to test for a causal relationship between serum urate (SU), gout, and prostate cancer. Using genome-wide association (GWAS) data, we generated instrumental variables (IVs) associated with gout and urate. These included 20 single nucleotide polymorphisms (SNPs) associated with gout but not urate (non-hyperuricemia compartment of gout) and four SNPs from loci containing urate transporter genes for an IV representing urate levels. MR methods included the inverse-variance weighted (IVW) method, MR-Egger regression, and the weighted median method. The non-hyperuricemia compartment of gout IV showed a causal effect of gout on prostate cancer (weighted median: p = 0.01). In contrast, the SU IV showed no evidence of a causal effect of SU on prostate cancer (IVW: p = 0.83; weighted median: p = 0.97). MR-Egger showed no evidence of horizontal pleiotropy (gout: p = 0.33; urate: p = 0.80). Loci contributing most strongly to the non-hyperuricemia causal effect included three genes: IL1R1, IL1RN, and SLC30A5. There was no evidence of a causal relationship between prostate cancer and gout or SU. In conclusion, MR analysis in a European male population found evidence of a causal relationship between the non-hyperuricemia compartment of gout and prostate cancer. Implication of the IL1R1 and IL1RN genes directly implicates the gouty inflammation pathway in prostate cancer. Full article

Background/Objective: Cutaneous melanoma is a highly heterogeneous malignancy and life-threatening skin cancer with rising global incidence. Although various therapeutic options are available, their clinical efficacy remains limited, highlighting the urgent need for novel strategies that facilitate prevention, diagnosis, and treatment. The aim of this study was to explore the potential causal association between medication use and the risk of developing cutaneous melanomas. Methods: Using summary data from Genome-Wide Association Studies (GWASs), we performed Mendelian randomization (MR) to investigate the causal effect of medication use on cutaneous melanoma risk. Exposure data were based on self-reported medication uses from ~320,000 European participants in the UK Biobank. The outcomes included GWAS results from 2824 cutaneous melanoma cases. Single-nucleotide polymorphisms (SNPs) significantly associated with medication use were used as instruments and analyzed with IVW, weighted median, weighted mode, and MR-Egger methods. Sensitivity analyses were used to assess pleiotropy and heterogeneity. Results: The analysis revealed that genetically predicted high use of adrenergics, inhalers, glucocorticoids, and opioids was suggestively associated with a reduced risk of cutaneous melanoma. Sensitivity analyses supported the robustness of these findings, showing no evidence of horizontal pleiotropy or influence from outliers. Conclusions: The results presented herein suggest that certain medication uses may lower the risk of developing cutaneous melanomas, offering potential new avenues for future prevention and treatment strategies. Full article

Obsessive–compulsive disorder (OCD) is a multifactorial condition, and interest in gut–brain interactions is increasing. We conducted a systematic two-step review, registered in PROSPERO (CRD420251083936). Step 1 mapped core OCD biology to gut-relevant pathways, including neuroimmune activation, epithelial barrier function, microbial metabolites, and stress circuitry, to clarify plausible mechanisms. Step 2 synthesized evidence from human and preclinical studies that measured or manipulated microbiota. Searches across PubMed, EMBASE, Web of Science, PsycINFO, and Cochrane (September 2025) yielded 357 biological and 20 microbiota-focused studies. Risk of bias was assessed using the Joanna Briggs Institute checklist for human studies and SYRCLE’s tool for animal studies. Although taxonomic findings in human cohorts were heterogeneous, functional patterns converged: reduced short-chain fatty acid capacity, enrichment of pro-inflammatory pathways, and host markers of barrier disruption and inflammation correlating with OCD severity. Transferring patient microbiota to mice induced OCD-like behaviors with neuroinflammatory changes, partly rescued by metabolites or barrier-supporting strains. Mendelian randomization suggested possible causal contributions at higher taxonomic levels. Diet, especially fiber intake, and psychotropic exposure were major sources of heterogeneity. Evidence supports the microbiota as a modifiable co-factor in a subset of OCD, motivating diet-controlled, stratified clinical trials with composite host–microbe endpoints. Full article

Acrylamide (ACR), a common dietary pro-oxidant generated in heat-processed foods, disrupts mitochondrial redox homeostasis. While its neurotoxic effects are recognized, the role of ACR in depression remains poorly understood. We hypothesized that dietary ACR exposure promotes depression via SIRT3-dependent mitochondrial oxidative injury. Through an integrative approach combining network toxicology (to prioritize candidate targets), transcriptomics, and Mendelian randomization (MR), we identified SIRT3 as the central mediator. Molecular dynamics simulations demonstrated that ACR’s primary metabolite glycidamide (GA) formed more stable and rigid complexes with key targets (including SIRT3, TP53, CASP3, JUN, PTGS2, and PTK2) than ACR itself, as evidenced by superior structural stability, reduced flexibility, and enhanced hydrogen bonding. Transcriptomic analysis of the human prefrontal cortex (datasets GSE54567 and GSE54568) revealed mitochondrial deacetylase sirtuin 3 (SIRT3) as the most significantly suppressed gene in depression (p < 0.01), suggesting an impairment in Superoxide dismutase 2 (SOD2)-mediated antioxidant defense. MR further established JUN and PTK2 as causal genetic risk factors for depression (JUN: Odds Ratio (OR) = 1.029, 95% CI = 1.002–1.057; PTK2: OR = 1.040, 95% CI = 1.005–1.076; JUN (OR) = 1.048, 95% CI = 1.021–1.076, PTK2: OR = 1.073, 95% CI = 1.039–1.109) of each MR estimates, while other candidates lacked genetic support. Our findings demonstrate that ACR induces depression primarily through SIRT3 suppression, activating JUN/PTK2 pathways, suggesting its potential role in environmental toxicant-induced redox imbalance. Full article

Studies have shown that the iron concentration in the peritoneal fluid of women is associated with the severity of endometriosis. Therefore, investigation of iron metabolism-related genes (IM-RGs) in endometriosis holds significant implications for both prevention and therapeutic strategies in affected patients. Differentially expressed IM-RGs (DEIM-RGs) were identified by intersecting IM-RGs with differentially expressed genes derived from GSE86534. Mendelian randomization analysis was employed to determine DEIM-RGs causally associated with endometriosis, with subsequent verification through sensitivity analyses and the Steiger test. Biomarkers associated with IM-RGs in endometriosis were validated using expression data from GSE86534 and GSE105764. Functional annotation, regulatory network construction, and immunological profiling were conducted for these biomarkers. Single-cell RNA sequencing (scRNA-seq) (GSE213216) was utilized to identify distinctively expressed cellular subsets between endometriosis and controls. Experimental validation of biomarker expression was performed via reverse transcription–quantitative polymerase chain reaction (RT-qPCR). BMP6 and SLC48A1, biomarkers indicative of cellular BMP response, were influenced by a medicus variant mutation that inactivated PINK1 in complex I, concurrently enriched by both biomarkers. The lncRNA NEAT1 regulated BMP6 through hsa-mir-22-3p and hsa-mir-124-3p, while SLC48A1 was modulated by hsa-mir-423-5p, hsa-mir-19a-3p, and hsa-mir-19b-3p. Immune profiling revealed a negative correlation between BMP6 and monocytes, whereas SLC48A1 displayed a positive correlation with activated natural killer cells. scRNA-seq analysis identified macrophages and stromal stem cells as pivotal cellular components in endometriosis, exhibiting altered self-communication networks. RT-qPCR confirmed elevated expression of BMP6 and SLC48A1 in endometriosis samples relative to controls. Both BMP6 and SLC48A1 were consistently overexpressed in endometriosis, reinforcing their potential as biomarkers. Moreover, macrophages and stromal stem cells were delineated as key contributors. These findings provide novel insights into therapeutic and preventive approaches for patients with endometriosis. Full article

Background: Intracranial aneurysm (IA) rupture is a life-threatening cerebrovascular event with a mortality rate of up to 40%, affecting approximately 500,000 people globally each year. Although environmental pollutants such as 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47) have been implicated in the pathogenesis of IA, the causal relationship and underlying mechanisms remain unclear. This study aims to systematically explore the potential causal role of PBDE-47 in the development of IA by integrating multi-omics approaches. Methods: We utilized the UK Biobank Drug Proteomics Project (UKB-PPP) genome-wide association study (GWAS) data, including 2940 plasma proteins and 1400 metabolites, along with IA genetic data from 456,348 individuals, to perform a two-sample Mendelian randomization (MR) analysis. Instrumental variables were selected based on genome-wide significance (p < 5 × 10⁻⁸) or suggestive thresholds (p < 5 × 10⁻⁵). Analytical methods included inverse variance weighting (IVW), MR-Egger, weighted median, MR-PRESSO, and Steiger filtering for sensitivity analysis. Molecular docking and 100-nanosecond molecular dynamics simulations were used to evaluate interactions between PBDE-47 and proteins. Mediation analysis assessed the roles of plasma metabolites and miRNAs, and SMR-HEIDI tests were used to verify causal relationships. Results: MR analysis identified 93 plasma proteins potentially causally associated with IA, including 53 protective factors and 40 risk factors. By integrating PBDE-47 targets, IA-related genes, and metabolite-related genes, we identified 15 hub genes. Molecular docking revealed potential binding between PBDE-47 and F2R (binding energy: −5.516 kcal/mol), and SMR-HEIDI testing supported F2R as a potential causal risk factor for IA. Molecular dynamics simulations indicated the stability of the complex structure. Mediation analysis suggested that F2R may influence IA risk through eight plasma metabolites, and miR-130b-3p may indirectly promote IA development by upregulating F2R. Conclusions: Our findings suggest that exposure to PBDE-47 may have a potential causal relationship with IA risk, potentially mediated through the “PBDE–47–F2R–metabolite–miRNA” regulatory axis. These results provide preliminary evidence for early diagnostic biomarkers and targeted interventions for IA. The multi-omics analytical framework established in this study offers new insights into environmental determinants of neurovascular diseases, although further validation is needed to address potential limitations. Full article

Background/Objectives: Classified as a hypertensive disorder of pregnancy, preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality. The abnormal trophoblast invasion that leads to a failed transformation of the uterine spiral arteries during placentation remains the most probable cause for preeclampsia. It is known that adiponectin acts on the placenta, playing a regulatory role in placentation processes. Therefore, the aim of this systematic review is to compile scientific evidence to evaluate the role of adiponectin as a biomarker for preeclampsia. Methods: The protocol for this systematic review was registered on the PROSPERO database (ID CRD42024542403) and follows the PRISMA 2020 guidelines. Overall, twenty-nine studies were selected from the PubMed and Scopus databases, including case–control, prospective and retrospective cohort, cross-sectional, and bidirectional Mendelian randomization studies. Results: From the articles analyzed, nine studies indicated an increase in adiponectin levels in preeclampsia, eleven reported a decrease, eight detected no significant changes, and in two studies, it was not possible to determine the glycoprotein levels. Analysis of the evidence quality revealed that moderate and low evidence levels predominate, with stronger evidence for decreased adiponectin levels. Conclusions: Promoting the advancement of scientific research is crucial, particularly exploring the association between adiponectin and other biomarkers. This approach could facilitate the development of screening and diagnostic methods, enabling the implementation of specific preventive and therapeutic strategies. Full article

Background: Colorectal cancer (CRC) is significantly associated with multiple metabolic diseases, with plasma metabolites potentially mediating this relationship. This large-scale metabolomics study aims to (1) quantify the genetic correlations and causal effects between 10 metabolic disease-related phenotypes and CRC risk; (2) identify the plasma metabolites mediating these effects; and (3) explore downstream regulatory genes and druggable targets. Methods: Using linkage disequilibrium score regression and two-sample Mendelian randomization, we assessed the causal relationships between each metabolic trait and CRC. A total of 1091 plasma metabolites and 309 metabolite ratios were identified and analyzed for mediating effects by a two-step MR approach. Colocalization analyses evaluated shared genetic loci. The findings were validated in the UK Biobank for metabolite-trait associations. The expression of candidate genes was explored using data from TCGA, GTEx, and GEO. A FADS1-centered protein–protein interaction (PPI) network was constructed via STRING. Results: BMI, waist circumference, basal metabolic rate, insulin resistance and metabolic syndrome exhibited both genetic correlation and causal effects on CRC. Five plasma metabolites—mannonate, the glucose/mannose ratio, plasma free asparagine, 1-linolenoyl-2-linolenoyl-GPC (18:2/18:3), and the mannose/trans-4-hydroxyproline ratio—were identified as shared central mediators. A colocalization analysis showed rs174546 linked CRC and 1-linolenoyl-2-linoleoyl-GPC. Validation in the UK Biobank confirmed the associations between phosphatidylcholine (the lipid class of this metabolite), adiposity measures, and CRC risk. An integrative analysis of TCGA, GTEx, and GEO revealed consistent upregulation of FADS1/2/3 and FEN1 in CRC, with high FADS1 expression predicting a poorer prognosis and showing the distinct cell-type expression in adipose and colon tissue. The PPI network mapping uncovered nine FADS1 interacting proteins targeted by supplements such as α-linolenic acid and eicosapentaenoic acid. Conclusions: This study systematically reveals, for the first time, the shared intermediary plasma metabolites and their regulatory genes in the causal pathway from metabolic diseases to CRC. These findings provide candidate targets for subsequent functional validation and biomarker development. Full article

Migraine is a complex neurological disorder that severely compromises quality of life. Current therapies remain inadequate, creating an urgent need for precision medicine approaches. To bridge this gap, we integrated genome-wide association studies (GWASs) and multi-tissue expression quantitative trait loci (eQTL) data. Using Mendelian randomization (SMR/HEIDI) to identify putatively causal genes, followed by colocalization analysis, protein–protein interaction networks, and gene enrichment, we prioritized druggable targets. Phenome-wide association studies (PheWASs) further assessed their potential safety profiles. We identified 31 migraine-associated genes in whole blood, 20 in brain tissue, and 9 genes shared by both whole blood and brain regions. Among 13 druggable genes identified from the DGIdb and supporting literature, 10 passed colocalization validation. Eight genes (TGFB3, CHRNB1, BACE2, THRA, NCOR2, NR1D1, CHD4, REV3L) showed interactions with known drug targets, enabling the computational prediction of 41 potential repurposable drugs. Based on target druggability, PPI (protein–protein interaction) and favorable PheWAS profiles, NR1D1, THRA, NCOR2, and CHD4 are prioritized for drug development. Additionally, MICU1, UFL1, LY6G5C, and PPP1CC emerged as novel pathophysiological factors. This study establishes a multi-omics framework for precision migraine therapy, translating genetic insights into clinically actionable targets. Full article

Metabolic reprogramming has recently been recognized as related to immune disorders in ulcerative colitis (UC), but the specific metabolic pathways and genes involved remain unclear. Here, Mendelian randomization confirmed that mannose and mannonate exhibited a negative causal relationship with UC, and that the immune cell phenotype HLA DR on CD33dim HLA DR+ CD11b− mediated the effect of mannonate on UC. Bulk RNA sequencing data revealed that mannose metabolism abnormity is critical for driving the innate and acquired immune response. A well-performing diagnostic model related to mannose metabolism was constructed using SVM analysis, achieving an AUC-ROC value of 0.987 in the training set and an AUC-ROC value of 0.899 in the validation set. Single-cell analysis revealed that epithelial cells in which the mannose metabolism pathway was inactivated demonstrated increased intercell communication with myeloid cells, T cells, and B cells. In vitro experiments confirmed that KHK and AKR1B10 were suppressed under inflammatory stimulation, which may hinder mannose-related metabolism. This study elucidates the protective role of mannose metabolism in UC and provides a novel gene signature for diagnosis and treatment. Full article

Background: Pregnancy-induced hypertension (PIH) affects approximately 10% of pregnancies worldwide, representing a leading cause of maternal and perinatal morbidity and mortality. The relationship between plasma selenium levels and PIH remains controversial, with observational studies limited by confounding factors. Selenoprotein S (SELENOS) has emerged as a potential biomarker for PIH risk. As one of the carrier proteins for dietary selenium, SELENOS plays a crucial role in oxidative stress and inflammatory pathways. However, the causal relationship between the plasma levels of the SELENOS and PIH development remains unclear. This study employed Mendelian randomization (MR) to investigate the causal link between the plasma levels of the SELENOS and PIH risk, providing evidence for preventive strategies. Methods: We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics from the INTERVAL study and FinnGen consortium. The analysis included individuals of European ancestry, utilizing the inverse-variance weighted (IVW) method as the primary approach. Comprehensive sensitivity analyses were performed to address potential pleiotropy and strengthen causal inference. Results: The analysis encompassed 3301 samples for the plasma levels of the SELENOS and 7686 PIH cases, 1109 pre-existing hypertension (PEH) cases, 4255 gestational hypertension (GH) cases, and 83 preeclampsia (PE) cases superimposed on chronic hypertension, alongside approximately 115,000 controls. Genetic variabilities that have been found to be accompanied by elevated levels of plasma selenioprotein levels showed significant associations with increased risk of PIH [odds ratio (OR) 1.078, 95% confidence interval (CI) 1.031–1.126, p = 0.001], PEH (OR 1.232, 95% CI 1.105–1.373, p < 0.001), and GH (OR 1.111, 95% CI 1.047–1.180, p = 0.001), with suggestive associations for preeclampsia superimposed on chronic hypertension (OR 1.590, 95% CI 1.078–2.344, p = 0.019). Conclusions: This study provides robust genetic evidence for a causal relationship between the plasma levels of the SELENOS and PIH risk, establishing SELENOS as a potential modifiable risk factor with significant clinical implications. These findings support the development of personalized selenium management strategies during pregnancy and highlight the potential for early screening and targeted interventions to improve maternal and fetal outcomes. Full article

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by immune-mediated β-cell destruction, where interleukin-6 (IL-6) signaling plays a complex and context-dependent role. Tocilizumab, an IL-6 receptor (IL-6R) inhibitor, is effective in several autoimmune conditions, but its influence on the onset and progression of T1DM remains uncertain. This scoping review aimed to map current clinical, genetic, and mechanistic evidence linking IL-6/IL-6R signaling to T1DM risk and to identify key research gaps. Following PRISMA-ScR guidelines, PubMed, Embase, and Web of Science were searched for studies from 2005 to 2025 reporting associations between tocilizumab or IL-6R modulation and T1DM onset. Six studies were included: one case report describing T1DM onset during tocilizumab therapy in a genetically predisposed patient, one randomized controlled trial showing no significant β-cell preservation with tocilizumab, three Mendelian randomization analyses with conflicting findings on IL-6R signaling, and one mechanistic study showing enhanced IL-6 responsiveness in early-stage T1DM. Collectively, evidence remains fragmented and inconclusive, highlighting research gaps in the differential roles of IL-6 classic versus trans-signaling and the impact of genetic predisposition. Future prospective studies should clarify whether selective IL-6 trans-signaling blockade may offer safer, targeted strategies for modulating autoimmune β-cell destruction. Full article

Atopic dermatitis (AD) and autoimmune diseases exhibit epidemiological comorbidity, yet the shared genetic architecture remains incompletely understood. We investigated the genetic overlap between AD and three autoimmune disorders including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and vitiligo, leveraging genome-wide association data. Despite modest evidence for global genetic correlations, we found 113 independent pleiotropic loci shared among AD and autoimmune diseases, with 11 displaying a concordant effect across all 3 pairwise comparisons. Gene-set and tissue enrichment analyses evidenced the inflammatory background of pleiotropic associations. Multi-trait colocalization analysis prioritized 22 loci, linking the tissue-specific expression of DOK2, GPR132, RERE, RERE-AS1, SUOX, TNFRSF11A, and TRAF1 pleiotropic genes with AD risk. Mendelian randomization revealed no causal effect of genetic liability to AD on autoimmune diseases. Nevertheless, genetic liability to IBD increased AD risk, while vitiligo exhibited a protective effect post outlier correction. Our findings provide mechanistic insights into the multimorbidity of atopic dermatitis (AD) and autoimmune diseases, offering additional evidence for the pleiotropic genetic architecture of AD that contributes to systemic immune dysregulation across multiple organ systems. Full article

The idea that gut microbes or a “bacillus of crime” might promote criminal behavior was popularized in the early 20th century. Today, advances in neuromicrobiology and related omics technologies are lending credibility to the idea. In recent cases of dismissal of driving while intoxicated charges, courts in the United States and Europe have acknowledged that gut microbes can manufacture significant amounts of systemically available ethanol, without a defendant’s awareness. Indeed, emergent research is raising difficult questions for criminal justice systems that depend on prescientific notions of free moral agency. Evidence demonstrates that gut microbes play a role in neurophysiology, influencing cognition and behaviors. This may lead to justice involvement via involuntary intoxication, aggression, anger, irritability, and antisocial behavior. Herein, we discuss these ‘auto-brewery syndrome’ court decisions, arguing that they portend a much larger incorporation of neuromicrobiology and multi-omics science within the criminal justice system. The legalome, which refers to the application of gut microbiome and omics sciences in the context of forensic psychiatry/psychology, will likely play an increasing role in 21st century criminal justice. The legalome concept is bolstered by epidemiology, mechanistic bench science, fecal transplant studies, multi-omics and polygenic research, Mendelian randomization work, microbiome signature research, and human intervention trials. However, a more robust body of microbiota–gut–brain axis research is needed, especially through the lens of prevention, intervention, and rehabilitation. With ethical guardrails in place, greater inclusion of at-risk or justice-involved persons in brain science and microbiome research has the potential to transform justice systems for the better. Full article

Background: Breast ductal carcinoma in situ (DCIS), a common precursor of breast cancer, has poorly understood susceptible driver genes. This study aimed to identify genes influencing DCIS progression by integrating Mendelian randomization (MR) and Gene Expression Omnibus (GEO) datasets. Methods: The GEO database was searched for DCIS-related datasets to extract differentially expressed genes (DEGs). MR was employed to find exposure single-nucleotide polymorphisms (SNPs) of expression quantitative trait locus (eQTL) gene expression from Genome-Wide Association Study database (GWAS) (IEU openGWAS project). DCIS was designated as the outcome variable. The intersection of genes was used for GO, KEGG and CIBERSORT analyses. The functional validation of selected DEGs was performed using Transwell invasion assays. Results: Four datasets (GSE7782, GSE16873, GSE21422, and GSE59246) and 19,943 eQTL exposure data were obtained from GEO and the IEU openGWAS project, respectively. By intersecting DEGs, 13 genes (LGALS8, PTPN12, YTHDC2, RNGTT, CYB5R2, KLHDC4, APOBEC3G, GPX3, RASA3, TSPAN4, MAPKAPK3, ZFP37, and RAB3IL1) were incorporated into subsequent KEGG and GO analyses. Functional assays confirmed that silencing PTPN12, YTHDC2 and MAPKAPK3, or overexpressing GPX3, RASA3 and TSPAN4, significantly suppressed DCIS cell invasion. These DEGs were linked to immune functions, such as antigen processing and presentation and the tumor microenvironment (TME), and they showed associations with dendritic cell activation differences. Conclusions: Thirteen genes were associated with DCIS progression, and six genes were validated in the cell experiments. KEGG and GO analyses highlight TME’s role in early breast cancer, enhancing understanding of DCIS occurrence and aiding identification of high-risk tumors. Full article