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PubMed2025

CAUSAL ASSOCIATION BETWEEN SEPSIS AND FIBROBLAST GROWTH FACTORS AS WELL AS THEIR RECEPTORS LEVELS: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY.

Objective: The potential association between sepsis risk and circulating levels of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been a focus of research; however, the causal relationship between them remains to be elucidated. We hypothesize a causal association between genetically predicted FGFs, FGFRs, and sepsis risk, and we conduct a Mendelian randomization (MR) study to validate this hypothesis. Methods: We utilized a two-sample MR design to assess the effect of genetic variants associated with various FGFs (FGF1, FGF2, FGF7, FGF16, FGF19, FGF21, FGF23, FGF5) and FGFRs (FGFR1, FGFR2, FGFR3, α-Klotho) on sepsis risk, using genome-wide association study summary statistics. Our MR analyses employed the inverse-variance weighted (IVW) method, along with weighted median, weighted mode, and MR-Egger regression, supplemented by sensitivity analyses to ensure robustness. Results: The MR analysis identified an unequal number of instrumental variables ranging from 2 to 17 for FGFs and FGFRs when sepsis was the outcome. No significant correlation was found between genetically determined FGF levels and sepsis risk by IVW analysis (all P > 0.05). Correspondingly, similar nonsignificant associations were observed for FGFRs (all P > 0.05). Other MR methods corroborated the IVW findings. Sensitivity analyses, including Cochran's Q test, MR-Egger, and MR pleiotropy residual sum and outlier, indicated no significant heterogeneity or pleiotropy in the relationships, with the exception of a nonsignificant correlation between FGFR1 and sepsis that persisted after the exclusion of an outlier (odds ratio, 0.84; P = 0.34). Conclusion: The analysis found no significant causal associations between FGFs, their receptors, and sepsis risk, indicating a need for further research on their complex interactions.

Humans↗

PubMed2026

Inflammatory cytokines mediate thoracic aortic aneurysm formation via plasma metabolites: A two-step Mendelian randomization and single cell sequencing-based investigation.

Thoracic aortic aneurysm (TAA) is a life-threatening condition characterized by pathological dilation of the aorta. While inflammatory responses have been implicated in TAA pathogenesis, the causal relationships remain elusive. This study aimed to elucidate potential causal associations between inflammatory cytokines, plasma metabolites, and TAA risk using Mendelian randomization (MR) analysis. We conducted bidirectional two-sample MR analysis utilizing genome-wide association study data from 91 inflammatory cytokines (n = 14,824), 1400 plasma metabolites (n = 8299), and TAA (n = 385,857). The inverse-variance weighted method served as the primary analytical approach, with comprehensive sensitivity analyses performed to assess pleiotropy and heterogeneity. Two-step MR analysis was employed to explore potential mediating roles of plasma metabolites. Single-cell sequencing analysis was utilized to detect cell type enrichment and elucidate cellular functions of identified cytokines. Additionally, we conducted an analysis to identify druggable proteins as potential therapeutic targets for TAA. MR analysis revealed that genetically-determined increases in C-X-C motif chemokine 10 (CXCL10) (odds ratios [OR] = 1.149, 95% confidence interval [CI]: 1.009-1.309, P = .037) and fibroblast growth factor 5 (OR = 1.101, 95% CI: 1.013-1.196, P = .024) were associated with elevated TAA risk. Conversely, C-C motif chemokine 20 (CCL20) (OR = 0.870, 95% CI: 0.759-0.996, P = .043) and CD40L receptor (CD40) (OR = 0.906, 95% CI: 0.827-0.992, P = .033) demonstrated inverse associations with TAA risk. Two-step MR analysis identified potential mediating metabolites: the phosphate to linoleoyl-arachidonoyl-glycerol ratio for CXCL10, thyroxine and X-24585 for FGF-5, and the creatine to carnitine ratio for CCL20. Single-cell sequencing analysis revealed enrichment of these cytokines in specific cell types and pathways relevant to TAA pathogenesis. Drug-gene interaction analysis identified CXCL10, CCL20, and CD40 as potential targets for treatment of TAA. This study provides robust genetic evidence supporting causal relationships between specific inflammatory cytokines and TAA risk, with plasma metabolites potentially mediating these effects. CXCL10 and FGF-5 were identified as potential risk factors, while CCL20 and CD40 may confer protective effects. These findings offer novel insights into TAA pathogenesis and suggest potential targets for intervention. Further research is warranted to elucidate the underlying mechanisms and validate these results across diverse populations.

Aortic Aneurysm, Thoracic↗

PubMed2026

Assessing the impact of maternal blood pressure during pregnancy on perinatal health: a wide-angled Mendelian randomization study.

BACKGROUND: Observational studies link high blood pressure in pregnancy to numerous adverse pregnancy and perinatal outcomes; however, findings may be affected by residual confounding or reverse causation. This study aimed to assess the causal effect of blood pressure during pregnancy on a range of pregnancy and perinatal outcomes. METHODS: We performed two-sample Mendelian randomization (MR) to assess the effect of systolic and diastolic blood pressure (SBP/DBP) during pregnancy on 16 primary and eight secondary adverse pregnancy and perinatal outcomes. We obtained genetic association data from large-scale meta-analyses of genome-wide association studies involving predominantly European ancestry individuals for SBP/DBP (N = 1,028,980), and pregnancy and perinatal outcomes (N = 74,368-714,899). We used inverse-variance weighted (IVW) MR for main analyses and MR-Egger, weighted median, weighted mode, multivariable MR, and IVW adjusted for fetal genetic effects for sensitivity analyses. RESULTS: A 10 mmHg higher genetically predicted maternal SBP increased the odds of gestational diabetes, induction of labour, low birth weight (LBW), small-for-gestational age (SGA), preterm birth (PTB), and neonatal intensive care unit (NICU) admission (OR ranging from 1.11 [95% CI 1.02 to 1.20] for NICU admission to 1.33 [1.26 to 1.41] for LBW); while decreasing the odds of high birth weight (HBW), large-for-gestational age (LGA), and post-term birth [OR ranging from 0.76 (0.69 to 0.83) for HBW to 0.94 (0.90 to 0.99) for post-term birth]. We did not find evidence that genetically predicted higher maternal SBP was related to miscarriage or stillbirth. The results for maternal DBP were similar to the results for SBP. Overall, the main results were consistent across sensitivity analyses accounting for pleiotropic instruments and fetal genetic effects. CONCLUSIONS: Higher maternal blood pressure reduces gestation duration and fetal growth and increases the risks of induction of labour, gestational diabetes, and neonatal intensive care unit admission. This and other emerging evidence highlight the value of interventions aimed at controlling blood pressure in the population to reduce the burden of adverse pregnancy outcomes.

Humans↗

PubMed2026

Investigating the causal effects of physical activity and sedentary behavior on hernia risk: A two-sample Mendelian randomization approach.

The global prevalence of hernia is increasing, particularly due to the aging population. Although physical activity and sedentary behavior are known to influence various health outcomes, their specific roles in hernia development remain inadequately investigated. This study aimed to systematically assess the causal relationships between physical activity, sedentary behavior, and the risk of hernia development using Mendelian randomization (MR) analysis. We used genome-wide association study data from the UK Biobank and FinnGen Biobank to explore the causal effects of sedentary behavior on hernia risk via 5 distinct MR approaches. To ensure the reliability of our risk models, we performed sensitivity analyses, including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Furthermore, we employed multivariable MR analysis to determine the independent causal effects of both physical activity and sedentary behavior. Our findings indicate that moderate-to-vigorous physical activity (MVPA) was significantly associated with an increased risk of inguinal hernia, with an odds ratio of 1.844 (95% confidence interval, 1.181-2.879; P = .007). Associations between sedentary behavior and diaphragmatic or umbilical hernia were inconsistent across methods and were sensitive to pleiotropy; thus, no robust causal relationship was established. Multivariable MR analysis further confirmed the independent and significant causal relationship between MVPA and inguinal hernia, with an odds ratio of 1.901 (95% confidence interval, 1.098-3.291; P = .022). Our study highlights a significant association between MVPA and an increased risk of inguinal hernia, suggesting that physical activity should be carefully considered in preventive strategies for hernias. However, the relationship between sedentary behavior and hernia development warrants further investigation.

Mendelian Randomization Analysis↗

PubMed2026

Mendelian Randomization Using a Japanese GWAS Identifies an HLA-Linked Causal Effect of Chronic Hepatitis B on Cholangiocarcinoma Risk.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer that develops in the bile ducts. Its incidence is particularly high in East Asian populations, but the underlying genetic factors remain unclear. To investigate potential risk factors for CCA, we conducted a Mendelian randomization study to infer causality. METHODS: Using large-scale genome-wide association study data from the BioBank Japan resource, we systematically investigated the causal effects of genetic predisposition to seven conditions, chronic hepatitis B (CHB), chronic hepatitis C, autoimmune hepatitis, type 1 diabetes, type 2 diabetes, chronic gastritis, and chronic pancreatitis, on CCA risk. RESULTS: Our analysis reveals a significant association between genetic susceptibility to CHB with a 24% higher likelihood of developing CCA than non-susceptible individuals (Inverse-Variance Weighted Odds Ratio = 1.24, 95% Confidence Interval: 1.08-1.42; p = 0.002). This genetic association is significantly driven by instrumental variables enriched in the immune-regulatory HLA class II region (6p21), suggesting a plausible biological mechanism. For the primary outcome (CCA), statistical significance was assessed across seven exposures at a Bonferroni-corrected threshold (two-sided p<0.0071). Notably, the CHB-CCA association remains significant after correction. This primary finding is strongly supported by comprehensive sensitivity analyses that showed no evidence of confounding by horizontal pleiotropy or heterogeneity. Conversely, no significant causal effects on CCA were identified for the other six conditions. CONCLUSIONS: Our MR analysis supports a causal role of HBV infection in CCA development, highlighting the importance of targeted HBV screening and surveillance.

Female↗

PubMed2026

Novel Insights into Immune Cell Function in Type 2 Diabetes Mediated by Gut Microbiota: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: The role of immune cells in type 2 diabetes mellitus (T2DM) development is well-studied, but their interactions with the gut microbiota and the mediating role in this process remain unclear. METHODS: We analyzed 731 immune cell phenotypes (3,757 Europeans), 473 gut microbiota traits (5,959 Finns), and T2DM data (over 400,000 Finns). Mendelian randomization (MR) was based on three assumptions: the instrumental variable (IV) is associated with exposure, IV is not influenced by confounding, and IV affects the outcome only through exposure. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies as instrumental variables (IVs) to infer causal effects in two-sample MR analysis. RESULTS: We identified 36 immune cell phenotypes associated with T2DM, including 29 protective factors and seven risk factors, as well as 10 gut microbiota significantly linked to T2DM, with eight protective factors and two risk factors. MR revealed that five gut microbiota mediated the relationship between immune cells and T2DM. For example, the effects of CD3 on resting Treg (OR: 1.0136), CD3 on CM CD4+ (OR: 1.0180), and CD3 on naive CD4+ cells (OR: 1.0150) in T2DM were found to be partially mediated by the species Bacillus. AYThe corresponding mediation effect proportions were 8.99%, 11.8%, and 11.4%. DISCUSSION: MR analysis identified multiple gut microbiota mediators in the relationship between immune cells and T2DM, addressing previous observational evidence. Limitations included the European ancestry bias, among others. CONCLUSION: This study has highlighted the gut microbiota as a mediator between immune cells and T2DM, offering new insights for its early prevention and intervention.

Diabetes Mellitus, Type 2↗

PubMed2026

Genetically predicted CXCL16 expression is associated with Parkinson's disease risk and peripheral immune cell dysregulation: a two-sample mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. PANoptosis, an integrated form of programmed cell death involving apoptosis, pyroptosis, and necroptosis, has been implicated in neuroinflammation-related neurodegeneration. However, the roles of PANoptosis-related genes in PD remain unclear. METHODS: We performed two-sample Mendelian randomization (MR) using cis-eQTL instruments from the eQTLGen Consortium for 30 PANoptosis-related genes, with PD GWAS data from Nalls et al. 2019 as the outcome. Instrumental variables were selected using a hierarchical strategy, with genome-wide significant cis-eQTLs as primary instruments and a relaxed threshold applied only for genes with fewer than three independent SNPs. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, MR-RAPS, and leave-one-out analyses. SMR/HEIDI testing and two-step MR mediation using 731 peripheral immune traits were also performed. RESULTS: Genetically predicted higher CXCL16 expression was associated with increased PD risk (OR = 1.115, 95% CI 1.060-1.173, p = 2.4 × 10-5), while higher FADD expression was associated with reduced PD risk (OR = 0.861, 95% CI 0.790-0.939, p = 7.1 × 10-4). CASP1 and IFI27 were nominally significant and considered exploratory. Sensitivity analyses were directionally consistent, although MR-Egger estimates were imprecise. SMR/HEIDI supported CXCL16. Exploratory mediation analysis identified 63/66 candidate immune mediators after FDR correction. CONCLUSION: These findings provide MR-based genetic evidence linking CXCL16 expression to PD risk, with exploratory mediation through peripheral immune phenotypes. The CXCL16-immune cell-PD axis warrants further experimental validation.

Humans↗

PubMed2024

Dissecting the association between blood pressure traits, hypertension, antihypertensive medications and epilepsy: A Mendelian randomization study.

BACKGROUND: Observational studies suggest that hypertension and epilepsy have a high co-occurrence, and antihypertensive medications may have impacts on the prevention and treatment of epilepsy. However, the directionality of causation between them is elusive. METHOD: By leveraging genome-wide association studies (GWAS) summary data of each trait, we firstly performed bidirectional univariate Mendelian randomization (UVMR) to assess the strength and direction of the associations between pairs of traits, then multivariate MR (MVMR) was conducted to adjust for potential confounders in causalities. Cochran's Q statistics, leave-one-out analysis, MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO) were employed to evaluate the robustness of the results. Drug target MR was proceeded to assess the association between five classes of first-line antihypertensive medications and epilepsy. Specifically, single nucleotide polymorphisms (SNPs) extracted from GWAS data on systolic blood pressure (SBP)/diastolic blood pressure (DBP), along with expression quantitative trait loci (eQTL) were utilized as proxies for antihypertensive medications, respectively. RESULTS: Forward UVMR results provided evidence that genetically predicted blood pressure traits and hypertension have causal effects on epilepsy, while reverse UVMR indicated no causal impacts of epilepsy on blood pressure traits or hypertension. The sensitivity analysis results were robust. The causalities between DBP, hypertension and epilepsy remained remarkable after adjustment by MVMR. Inverse-variance-weighted MR (IVW-MR) yielded evidence of positive association only between Beta-Blockers target genes based on DBP GWAS screening and epilepsy. Summary-data-based MR (SMR) identified a positive correlation between Beta-Blockers target gene ADRA1D and epilepsy risk. CONCLUSIONS: Hypertension has a causal effect on epilepsy and managing DBP in patients with hypertension through Beta-Blockers may help prevent epilepsy.

Humans↗

PubMed2024

Relationship between inflammation/immunity and epilepsy: A multi-omics mendelian randomization study integrating GWAS, eQTL, and mQTL data.

OBJECTIVES: Increasing evidence suggests that activated innate/adaptive immunity induces an inflammatory response, thereby participating in epileptogenesis. However, the biological explanation of inflammation/immunity as a potential cause for epilepsy remains largely unknown. This research aimed to determine the causal effects of inflammation/immune-related genes in epilepsy based on multi-omics mendelian randomization (MR). METHODS: We employed summary-data-based MR (SMR) approach to combine GWAS for epilepsy (12,891 cases and 312,803 control) with gene expression quantitative trait loci (cis-eQTL, 31,684 participants) and DNA methylation QTL (cis-mQTL, 1,980 participants) data. Five additional MR methods were then used for sensitivity analyses to confirm the reliability of causal associations. In addition, enrichment analysis of key genes was conducted to provide insight into the biological functions of epilepsy risk variants. RESULTS: A total of 386 inflammation/immune-related genes were selected for further analyses. Primary SMR analysis indicated that 37 DNA methylation sites and six genes regulated by them had potential causal relationship with epilepsy. MR analysis further refined the results, identifying three genes that had a causal effect on epilepsy. Notably, VEGFA (OR: 0.925; 95 % CI: 0.862-0.994) expression was negatively correlated with epilepsy risk, whereas IL16 (OR: 1.076; 95 % CI: 1.028-1.126) and HLA-DPA1 (OR: 1.041; 95 % CI: 1.009-1.074) expressions were positively associated with epilepsy risk. Functional enrichment analysis revealed that the identified genes were involved in GO-BP terms related to VEGF activation signaling and chemotaxis regulation. CONCLUSION: This analysis confirms the causal role of inflammation/immunity in epilepsy, and the identified candidate genes provide clues for drug development in clinical practice.

Humans↗

PubMed2026

Single-cell expression quantitative trait locus Mendelian randomization reveals immune cell-specific causal regulatory networks and actionable targets in polycystic ovary syndrome.

ObjectiveTo systematically investigate whether the pathogenesis of polycystic ovary syndrome (PCOS) is causally related to dysregulated gene expression in specific immune cell subsets, and to evaluate the potential of these causal genes as actionable drug targets.MethodsThis study employed a two-sample Mendelian randomization (MR) framework using publicly available genome-wide association study (GWAS) summary statistics. The participant data included 797 PCOS cases and 140,558 controls (no direct patient recruitment was involved). Instrumental variables were derived from high-resolution immune cell-specific single-cell expression quantitative trait locus (sc-eQTL) data (OneK1K project) across 14 immune cell types. Primary analyses utilized the inverse-variance weighted (IVW) method. Shared causal variants were validated using Bayesian colocalization. Phenome-wide association analysis (PheWAS), external transcriptomic dataset validation (GSE8157), and DrugBank database screening were conducted for pleiotropy assessment and drug repositioning.ResultsMR analysis revealed genome-wide significant causal associations for GLIPR1 in non-classical monocytes (Mono NC) and XBP1 in CD4+ effector memory T cells (CD4 ET) with PCOS risk. Higher GLIPR1 expression was associated with a decreased PCOS risk (OR = 0.669, P = 4.34×10-6), whereas higher XBP1 expression was associated with an increased risk (OR = 1.406, P = 9.53×10-8). Colocalization analysis confirmed that GLIPR1 shares a causal variant with PCOS (PP.H4 = 96.73%). PheWAS and external validation confirmed the safety profile and significant upregulation (P = 0.03) of GLIPR1. Drug repositioning identified SOT-107, a Phase III protein therapy drug, as a potential interacting agent for GLIPR1.ConclusionsThis sc-eQTL MR study reveals immune cell-specific causal regulatory networks in PCOS. GLIPR1 in non-classical monocytes represents a high-confidence protective target, while XBP1 provides suggestive evidence for immune-mediated pathogenesis. The candidate drug SOT-107 highlights theoretical repositioning opportunities, though rigorous preclinical validation remains required.

Female↗

PubMed2026

The Association of Allergic Rhinitis with Chronic Adenotonsillar Diseases and Chronic Rhinosinusitis: A Mendelian Randomization Study.

INTRODUCTION: Allergic rhinitis (AR) has long been considered to be associated with chronic adenotonsillar disease (CATD). However, their causal relationship remains unclear. This study aims to investigate the causal relationship between AR and CATD and to examine the mediating role of chronic rhinosinusitis (CRS) in this association. METHODS: This study employed a two-sample Mendelian randomization (MR) design using genetic instrumental variable analysis. Data for allergic rhinitis (AR) were obtained from the MRC IEU OpenGWAS data infrastructure, data for chronic adenotonsillar disease (CATD) from the FinnGen biobank, and data for chronic rhinosinusitis (CRS) from the GWAS Catalog. Several MR methods were applied. In addition, a two-step MR approach was used to investigate the mediating role of CRS in the relationship between AR and CATD. RESULTS: MR analysis identified a positive correlation between AR and CATD. IVW and weighted median analyses showed significant causal effects (beta = 0.55, 95% CI: 0.26 to 0.84); p <0.001). No causal association was found between CATD and AR. AR and CRS showed a positive correlation (beta = 1.38, 95% CI: 0.78 to 1.98; p = 6.5 × 10-6). CRS had a beta value of 0.15 (95% CI: 0.06 to 0.24; p = 0.001) for CATD. CRS mediates 37.6% of the AR to CATD pathway (mediation effect = 0.20, 95% CI: 0.04 to 0.37; p = 0.013). DISCUSSION: These findings indicate that AR may contribute to CATD risk through CRS, highlighting the need for further research to explore underlying biological mechanisms and validate these findings. CONCLUSIONS: This study suggests a positive causal relationship between AR and CATD, with CRS acting as a mediator.

Mendelian Randomization Analysis↗

PubMed2025

Association between gynecological cancers and female infertility: insights from bidirectional Mendelian randomization analysis.

PURPOSE: In recent years, research interest in the potential link between female infertility (FI) and gynecological cancer (GC), including ovarian cancer (OC), endometrial cancer (EC), cervical cancer (CC), and breast cancer (BC), has grown, yet findings remain inconclusive. This study aims to explore the causal relationship between FI and GC using bidirectional two-sample Mendelian randomization (MR) analyses, thereby informing future strategies for FI and GC prevention. METHODS: We utilized SNPs identified from genome-wide association studies (GWAS) on FI and GC. The inverse variance weighted (IVW) method served as the primary approach to assess the causal association between FI and GC. Additionally, five other MR methods-Weighted median, Weighted mode, MR-Egger, Simple mode, and Robust-Adjusted Profile Score-were employed to enhance result robustness and credibility. RESULTS: In the forward MR analysis, our IVW results indicated no significant association between FI and GC (FI-BC: OR = 0.95, 95% CI: 0.83-1.09, P = 0.47, P-FDR = 0.775; FI-OC: OR = 1.01, 95% CI: 0.84-1.24, P = 0.789, P-FDR = 0.896; FI-CC: OR = 0.80, 95% CI: 0.61-1.06, P = 0.118, P-FDR = 0.775; FI-EC: OR = 1.07, 95% CI: 0.88-1.30, P = 0.490, P-FDR = 0.775).In the reverse MR analysis, we found a marginal association between BC and FI. However, after adjusting for multiple testing using the FDR method, no significant causal relationship was found between BC and FI, suggesting a marginal association (OR = 1.054, 95% CI: 1.001-1.108, P = 0.043, P-FDR = 0.331). For other cancers, no significant causal relationships were observed between OC, CC and EC with FI(OC-FI: OR = 1.043, 95% CI: 0.999-1.087, P = 0.051, P-FDR = 0.331;CC-FI: OR = 0.992, 95% CI: 0.956-1.028, P = 0.654, P-FDR = 0.836; EC-FI: OR = 1.006, 95% CI: 0.956-1.055, P = 0.809, P-FDR = 0.885). CONCLUSIONS: Our study found no significant causal relationship between FI and GC. However, a potential marginal association between BC and FI was observed. These findings underscore the need for further research to confirm this association and emphasize the importance of reproductive protection for young breast cancer patients to preserve fertility.

Humans↗

PubMed2025

Is there a genetic correlation between tinnitus and temporomandibular joint disorder?: A two-sample Mendelian randomization study.

Tinnitus and temporomandibular disorder (TMD) are frequent coexistence of clinical symptoms caused by some systemic diseases in all humans. The observational research results on the correlation between tinnitus and TMD are inconsistent with the reported findings. The purpose of the study was to explore the bidirectional causal relationship between tinnitus and TMD. This study adopts a two-sample Mendelian randomization (MR) methodology. Single-nucleotide polymorphisms from the genome-wide association study were used as instrumental variables to elucidate the bidirectional causal relationship between tinnitus and TMD. The quality of our study was evaluated in accordance with the STROBE-MR guidelines. The MR analysis results showed that tinnitus (yes, most or all of the time now) could be significantly reduced TMD muscular pain linked with fibromyalgia (OR = 0.239, 95% CI: 0.087-0.66, P = .0057), but there was no correlation between other frequencies of tinnitus and the increased risk of TMD in genetic predisposition (all P > .05). The reverse MR analysis revealed no causal relationship and correlation between TMD exposure and increased risk of tinnitus. Sensitivity analysis indicated no horizontal pleiotropy and insignificant heterogeneity. This MR study supports evidence of a correlation between high-frequency tinnitus and reduced risk of TMD muscle pain associated with fibromyalgia. Further research on disease mechanisms are needed to explore the correlation between tinnitus and TMD.

Humans↗

PubMed2026

A 2-step, 2-sample Mendelian randomization study of gut microbiota, blood metabolites and dry age-related macular degeneration.

Dry age-related macular degeneration (dAMD) is the leading cause of blindness among elderly people in developed countries. The main objective of this study is to investigate the causal relationship between gut microbiota (GM), blood metabolites, and dAMD among European participants. Based on the genome-wide association analysis database, double sample Mendelian randomization (MR) analysis was performed on GM, blood metabolites, and dAMD. The inverse-variance weighted method is used to estimate the causal relationship between GM, blood metabolites, and dAMD, while multiple methods are employed to eliminate pleiotropy and heterogeneity. A 2-step MR analysis quantitatively assessed the effect of metabolite-mediated GM on dAMD. In MR analysis, 15 GM were found to be associated with increased or decreased risk of dAMD, and 18 blood metabolites were found to be associated with increased or decreased risk of dAMD. Our research also found that the potential association between GM and dAMD may be mediated by blood metabolite levels, specifically, ADpSGEGDFXAEGGGVR levels accounted for 38.9% of the causal pathway from genus Parasutterella to dAMD. Our research findings indicate that certain GM and blood metabolites can affect the onset of dAMD, and increasing the abundance of genus Parasottella can increase the risk of dAMD through the mediation of ADpSGEGDFXAEGGGVR levels.

Humans↗

PubMed2026

Causal relationships between psoriasis and coronary artery disease: A two-sample Mendelian randomization study.

Previous studies have revealed a potential association between psoriasis and coronary artery disease (CAD). However, the causal relationship between the 2 remains unclear. This study aims to assess the causal link between psoriasis and CAD, which encompasses coronary heart disease, myocardial infarction, and angina pectoris. After obtaining genome-wide association studies data on psoriasis and CAD, we selected appropriate single nucleotide polymorphisms for Mendelian randomization (MR) analysis. The inverse-variance weighted method was used as the main analytical method. The inverse-variance weighted method indicated that psoriasis was associated with a higher risk of CAD (odds ratio = 11.538, 95% confidence interval = 4.498-29.595, P < .001), and coronary heart disease (odds ratio = 1.080, 95% confidence interval = 1.031-1.132, P = .001). Reverse MR analyses did not show causal effects of CAD on psoriasis. This study shows a significant causal association between psoriasis and incidence of CAD. However, there is no reverse causal association between CAD and psoriasis.

Psoriasis↗

PubMed2026

The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. RESULTS: GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10- 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10- 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10- 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region. CONCLUSIONS: This study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.

Humans↗

PubMed2026

Genetic and epigenetic underpinnings of biological aging: a multi-omics study integrating Mendelian randomization, spatial transcriptomics, and drug target discovery.

Inflammaging represents a hallmark of biological aging, yet the causal inflammatory mediators driving multi-dimensional epigenetic aging and their effector genes remain poorly characterized at the genetic level. We developed a four-tier analytical framework integrating causal screening, multi-omics effector gene mapping, spatial transcriptomics, and drug target evaluation. Two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins against six aging phenotypes identified IL-12B, IFNG, and IL-2 as the most robust pro-aging mediators with consistent effects across independent outcomes. Using multi-omics summary-based MR (SMR) as the core analytical engine, we integrated four-layer whole-blood molecular QTL resources eQTL (eQTLGen, n = 31,684), sQTL (GTEx, n = 755), pQTL (INTERVAL + SCALLOP, n = 34,232), and mQTL (McRae et al., n = 1,980) - with GWAS summary statistics for four epigenetic age acceleration measures. At a stringent threshold (P_SMR < 1×10⁻¹²), seven high-confidence effector genes were identified: NHLRC1, TPMT, SELP, and RIPPLY3 for IEAA; ZNF373A and PLDN for HannumAA; and EDARADD for PhenoAA. The chromosome 6p21 NHLRC1-TPMT locus, overwhelmingly driven by methylation QTL signals (-log₁₀P = 26.06), emerged as the dominant genetic node of epigenetic aging. Spatial projection via gsMap onto a mouse E16.5 embryo atlas (121,767 cells) revealed preferential enrichment in smooth muscle and lung, with EDARADD showing marked specificity in mucosal epithelium. Cross-database drug target mining classified TPMT and SELP as repurposable known targets and NHLRC1 as a high-priority novel druggable candidate. This study provides multi-omics convergent causal evidence for inflammation-driven epigenetic aging and delivers genetically anchored targets for precision anti-aging intervention.

Aging↗

PubMed2026

Toxicological effects of propyl 4-hydroxybenzoate on gallstone pathogenesis: An integrated mendelian randomization, network toxicology, and experimental study.

BACKGROUND: Gallstone disease is a prevalent digestive disorder with substantial global socioeconomic burden. Propyl 4-hydroxybenzoate (PP), a widely used paraben preservative, exhibits potential metabolic and hepatic toxicity, yet its role in gallstone pathogenesis remains unclear. This study aimed to explore the causal association between PP exposure and gallstone formation and the underlying mechanism. METHODS: Two-sample Mendelian randomization (MR) was performed using genome-wide association study (GWAS) data. Network toxicology, molecular docking, and molecular dynamics simulation were applied to screen for core targets. In vivo experiments, transcriptome sequencing, Western blot (WB), and ELISA were conducted for mechanistic validation. RESULTS: MR confirmed a causal link between circulating PP levels and an elevated risk of gallstones (P < 0.05), with AKT1 identified as the key target. In mice, PP aggravated gallstone formation by activating the AKT1-NF-κB-CXCL1 pathway, enhancing hepatic inflammation and neutrophil extracellular traps (NETs) formation; these effects were reversed by AKT inhibition. CONCLUSION: PP promotes gallstone formation via the AKT1-NF-κB-CXCL1-NETs axis. Our findings highlight PP as an environmental risk factor for gallstones, providing novel insights into their prevention and targeted therapy.

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