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PubMed2026

Deciphering the Microbiome-Gut-Eye Axis: A Mendelian Randomization Analysis of the Causal Influence of Gut Microbiota on Myopia.

INTRODUCTION: The intricate relationship between the gut microbiome and myopia is increasingly recognized, underscoring the need to explore its causal dynamics. Despite emerging evidence, the influence of Gut Microbiota (GM) on ocular development remains underexplored. METHODS: This study utilized Mendelian Randomization (MR) to investigate the causal impact of GM on the development of myopia. Instrumental variables (IVs) were identified from Genome-Wide Association Studies (GWAS), focusing on genetic variants significantly associated with microbiome composition. A comprehensive array of MR techniques was applied to ensure a robust estimation of causal effects and to adjust for potential confounders and pleiotropy. RESULTS: The Inverse-Variance Weighted (IVW) method was used to identify significant associations between GM and myopia. Increased risk of myopia was linked to the class Betaproteobacteria (OR=1.01, 95% CI 1.004-1.017, P=0.003), the order Burkholderiales (OR=1.009, 95% CI 1.001-1.016, P=0.02), the family Oxalobacteraceae (OR=1.005, 95% CI 1.001-1.01, P=0.023), and several genera including Eubacterium xylanophilum group (OR=1.007, 95% CI 1.001-1.013, P=0.033), and Bifidobacterium (OR=1.005, 95% CI 1-1.01, P=0.038). Protective effects were noted for the order Mollicutes RF9 (OR=0.994, 95% CI 0.99-0.999, P=0.014), the genus Allisonella (OR=0.996, 95% CI 0.993-0.999, P=0.019), the genus Lachnospiraceae UCG001 (OR=0.994, 95% CI 0.989-1, P=0.045), and the family Enterobacteraceae (OR=0.991, 95% CI 0.982-1, P=0.047) and order Enterobacteriales (OR=0.991, 95% CI 0.982-1, P=0.047). Sensitivity analyses further confirmed the robustness of these findings. DISCUSSION: This study provides causal evidence for the "Microbiome-Gut-Eye Axis" in myopia development, identifying specific gut microbiota that influence myopia risk. These findings suggest potential for microbiota-targeted interventions, warranting further research in diverse populations. CONCLUSIONS: The findings support the "Microbiome-Gut-Eye Axis" as a potential factor in myopia pathogenesis and highlight microbiota-targeted interventions as novel therapeutic strategies for managing myopia. This study lays the groundwork for further research on how modifying GM can influence eye health and offers new perspectives on preventive health strategies.

Humans↗

PubMed2025

Mendelian randomization underscores the importance of clinical nursing in mitigating anxiety and panic attack risks among low-educated populations.

Considering the complex and underexplored interplay between educational attainment (EA) and the prevalence of anxiety and panic attacks, which carries significant societal implications, we have designed a two-sample Mendelian randomization (MR) study. The primary objective of this research is to elucidate the causal relationship between education level and the risk of anxiety and panic attacks, thereby providing novel insights for clinical and nursing strategies. Our study adheres to the STROBE-MR guidelines and employs a classical two-sample MR analysis to investigate the causal relationship between EA (exposure) and the occurrence of anxiety/panic attacks (outcome). The data for 8 education-related phenotypes, along with anxiety and panic attack outcomes, were sourced from European population-based Genome-wide association studies databases. To ensure robustness, we applied 5 distinct MR analytical methods, supplemented by comprehensive sensitivity analyses, heterogeneity assessments, and evaluations of reverse causality bias to uphold rigorous quality control standards. Our findings, robust across various MR methods and consistent after inverse variance-weighted and false discovery rate (FDR) corrections, indicate a significant association between lower EA and an increased risk of anxiety or panic attacks. Specifically, individuals with no formal qualifications exhibited a higher risk (P-value = .005, OR = 1.017, 95% CI = 1.005-1.029, FDR = 0.011). In contrast, higher levels of education were associated with a reduced risk: College or University degree (P-value < .01, OR = 0.989, 95% CI = 0.984-0.995, FDR = 0.0007), EA (P-value < .01, OR = 0.999, 95% CI = 0.998-0.9995, FDR = 0.0009), and A levels/AS levels or equivalent (P-value = .011, OR = 0.988, 95% CI = 0.978-0.997, FDR = 0.019). These conclusions were consistently supported by at least 4 MR methods and successfully passed all quality control checks. Our study demonstrates a negative correlation between years of education and the risk of anxiety and panic attacks, suggesting that clinical nursing and patient education efforts should prioritize tailored psychological support and patient communication for individuals with lower EA. This population warrants enhanced attention and more compassionate care to mitigate their elevated risk of anxiety-related disorders.

Humans↗

PubMed2025

Blood Pressure Lowering and Risk of Cancer: Individual Participant-Level Data Meta-Analysis and Mendelian Randomization Studies.

BACKGROUND: Pharmacologic blood pressure (BP) lowering is typically a lifelong treatment, and both clinicians and patients may have concerns about the long-term use of antihypertensive agents and the risk for cancer. However, evidence from randomized controlled trials (RCTs) regarding the effect of long-term pharmacologic BP lowering on the risk for new-onset cancer is limited, with most knowledge derived from observational studies. OBJECTIVES: The aim of this study was to assess whether long-term BP lowering affects the risk for new-onset cancer, cause-specific cancer death, and selected site-specific cancers. METHODS: Individual-level data from 42 RCTs were pooled using a one-stage individual participant data meta-analysis. The primary outcome was incident cancer of all types, and secondary outcomes were cause-specific cancer death and selected site-specific cancers. Prespecified subgroup analyses were conducted to assess the heterogeneity of the BP-lowering effect by baseline variables and over follow-up time. Cox proportional hazards regression, stratified by trial, was used for the statistical analysis. For site-specific cancers, analyses were complemented with Mendelian randomization, using naturally randomized genetic variants associated with BP lowering to mimic the design of a long-term RCT. RESULTS: Data from 314,016 randomly allocated participants without known cancer at baseline were analyzed. Over a median follow-up of 4 years (Q1-Q3: 3-5 years), 17,954 participants (5.7%) developed cancer, and 4,878 (1.5%) died of cancer. In the individual participant data meta-analysis, no associations were found between reductions in systolic or diastolic BP and cancer risk (HR per 5 mm Hg reduction in systolic BP: 1.03 [95% CI: 0.99-1.06]; HR per 3 mm Hg reduction in diastolic BP: 1.03 [95% CI: 0.98-1.07]). No changes in relative risk for incident cancer were observed over follow-up time, nor was there evidence of heterogeneity in treatment effects across baseline subgroups. No effect on cause-specific cancer death was found. For site-specific cancers, no evidence of an effect was observed, except a possible link with lung cancer risk (HR for systolic BP reduction: 1.17; 99.5% CI: 1.02-1.32). Mendelian randomization studies showed no association between systolic or diastolic BP reduction and site-specific cancers, including overall lung cancer and its subtypes. CONCLUSIONS: Randomized data analysis provided no evidence to indicate that pharmacologic BP lowering has a substantial impact, either increasing or decreasing, on the risk for incident cancer, cause-specific cancer death, or selected site-specific cancers.

epidemiology↗

PubMed2026

Single-Cell Transcriptome-Wide Mendelian Randomization and Colocalization Uncover Potential Immunocytes-Related Therapeutic Targets for Obesity.

Weight-loss treatment is crucial for individuals with obesity to prevent various complications. The role of Immune cells in obesity has been recently recognized, whereas its translation into therapy requires identifying key target genes. We performed Mendelian randomization (MR) analysis to assess causal relationships between expression quantitative trait loci (eQTL) of 14 immune cells and obesity-related traits (obesity, body mass index and body fat percentage), and validated the results in colocalization analysis. For the putative causal genes identified by the MR and colocalization analyses, we conducted pathway enrichment, differential expressed gene (DEG) analysis and search of druggable evidence, and utilized a Tier system to prioritize drug targets for obesity. MR and colocalization evidence was observed for 1630 genes associated with one or more obesity-related traits, mainly expressed in CD4+ naive/central memory T cells and enriched in antigen processing and presentation pathways. Forty-one genes showed causal relationship with all three outcomes, among which 19 genes have not been reported for obesity previously. DEG analysis using single-cell RNA sequencing data of blood or adipose tissue indicated that the differential expression of UBE2Z in monocytes, ZCCHC7 in T cells, and FNBP4 in B cells between lean and obese individuals were consistent with the MR results. By searching drug-gene interaction databases, we found targeted drugs for PYGB and PRUNE1, and PYGB was the top gene ranked in the Tier system. This study provides evidence for the involvement of immune cells in obesity, and the potential cell-specific, immune-related targets for obesity treatment.

Obesity↗

PubMed2025

THE CAUSAL ASSOCIATION OF CARDIOMETABOLIC DISEASES AND SEPSIS-RELATED OUTCOMES: A MENDELIAN RANDOMIZATION AND POPULATION STUDY.

Objective: The causality between cardiometabolic disease (CMD) and sepsis has remained largely unknown. To elucidate this, we conducted a Mendelian randomization (MR) and population study. Methods: First, we used univariable and multivariable MR analyses to investigate causal associations between CMD and sepsis-related outcomes. We obtained genome-wide association study summary from both the MRC Integrative Epidemiology Unit and the FinnGen consortium. Subsequently, a two-step mediation MR analysis was performed to explore mediators. Afterward, we conducted an observational study using the Medical Information Mart for Intensive Care IV database, in which multivariable logistic regression models were utilized to examine the relationship between CMD and sepsis-related outcomes. Results: In the MR study, type 2 diabetes mellitus (OR = 1.058, 95% CI = 1.017-1.100, P = 0.005), obesity (OR = 1.113, 95% CI = 1.057-1.172, P < 0.001), and heart failure (HF) (OR = 1.178, 95% CI = 1.063-1.305, P = 0.002) were independently causally related to sepsis. Obesity (OR = 1.215, 95% CI = 1.027-1.437, P = 0.023) and HF (OR = 1.494, 95% CI = 1.080-2.065, P = 0.015) also showed independent causal associations with sepsis critical care admission. Mediation MR analysis identified 23 blood metabolites potentially causally linked to sepsis ( P < 0.05), yet none mediated the relationship between CMD and sepsis. In the observational study, we found associations between sepsis and several conditions including type 2 diabetes mellitus, obesity, hypertension, stroke, HF, and hyperlipidemia after adjusting for confounding factors. Moreover, hypertension, stroke, HF, coronary artery disease, and hyperlipidemia were linked to sepsis critical care admission. Conclusion: This study has, for the first time, revealed indicative evidence of a causal relationship between CMD and sepsis through observational and genetic evidence. Taken together, clinical attention to sepsis may be warranted among patients with CMD.

Humans↗

PubMed2026

The causal effect of juvenile idiopathic arthritis on IgA nephropathy: A Mendelian randomization study.

IgA nephropathy (IgAN) has been documented in patients with various comorbidities. Previous observational studies showed an association between juvenile idiopathic arthritis (JIA) and IgAN. The aim of this study was to determine whether there is a causal effect of JIA on the risk of IgAN using a 2-sample Mendelian randomization (MR) approach. A 2-sample MR analysis was conducted to elucidate the potential causal relationship between JIA and IgAN. Summary-level data from genome-wide association studies in the European population were utilized, including IgAN (5556 cases and 21,178 controls) and JIA (3305 cases and 9196 controls). The inverse variance weighted method showed significant evidence of a positive causal relationship between genetically predicted JIA and IgAN. For each standard deviation increase in genetically predicted JIA, the risk of IgAN was found to be increased by 22% (odds ratio [OR] = 1.22, 95% CI: 1.10-1.29, P = 3.03 × 10-4). Similar associations were observed with the weighted median (OR: 1.16, 95% CI: 1.05-1.29) and weighted mode methods (OR: 1.16 95% CI: 1.02-1.33), but not with the simple median (OR: 1.22, 95% CI: 0.99-1.50) and MR Egger method (OR: 1.21, 95% CI: 0.93-1.57). Reverse MR analysis found no inverse causal relationship between these 2 diseases. This study provides genetic evidence supporting a causal link between JIA and an increased risk of IgAN. In JIA patients, periodic evaluation of kidney function and proteinuria is warranted.

Humans↗

PubMed2026

Genetic Evidence That Stroke Causally Increases Circulating PDGFB Levels: a Two-Sample Mendelian Randomization Study.

Platelet-derived growth factor subunit B (PDGFB) is a key regulator of vascular remodeling, angiogenesis, and blood-brain barrier integrity. Although elevated PDGFB levels have been reported after ischemic injury, whether stroke liability itself causally influences circulating PDGFB levels remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically predicted all stroke, ischemic stroke, and cardioembolic stroke on plasma PDGFB concentrations. Genetic instruments were obtained from large-scale GIGASTROKE genome-wide association studies, and outcome data were derived from a proteomics GWAS. Instruments were then filtered by removing variants associated with established cardiovascular risk factors in a phenome-wide screen and outliers identified by RadialMR. The inverse variance-weighted (IVW) method was used as the primary analysis, complemented by weighted median, weighted mode, and MR-Egger approaches. Sensitivity analyses included Cochran's Q statistics, MR-Egger intercept tests, single-SNP analyses, leave-one-out analyses, and MR-PRESSO. IVW analysis demonstrated a significant positive causal association between genetic liability to all stroke and plasma PDGFB levels (β = 0.209, SE = 0.062, 95% CI 0.088 to 0.331, p = 7.3 × 10-4). A similar association was observed for ischemic stroke (β = 0.155, SE = 0.059, 95% CI 0.039 to 0.270, p = 0.009), with directionally consistent results across sensitivity analyses. MR-Egger regression for ischemic stroke initially suggested pleiotropy.After removal of a radial-MR outlier (rs2289252), the intercept was attenuated and no longer statistically significant (- 0.0190, p = 0.282). In contrast, no evidence of a causal association was found between cardioembolic stroke liability and plasma PDGFB levels across all MR methods (β = - 0.078, SE = 0.087, 95% CI - 0.248 to 0.092, p = 0.368). These findings provide genetic evidence that liability to stroke, particularly ischemic stroke, is causally associated with increased circulating PDGFB levels, whereas cardioembolic stroke does not show such an effect. This suggests that elevated PDGFB reflects vascular responses specific to ischemic stroke rather than a general consequence of all stroke subtypes.

Humans↗

PubMed2026

Bayesian Mendelian randomization reveals a protective effect of later age at first sexual intercourse against erectile dysfunction.

Erectile dysfunction (ED) is a prevalent health condition with significant psychosocial impacts, yet the causal role of age at first sexual intercourse (AFS) remains unclear. This study investigated the causal effect of AFS on the risk of ED using Mendelian randomization (MR) and Bayesian methods. Five traditional 2-sample MR analyses and 5 Bayesian MR analyses were performed using genome-wide association studies summary statistics from European populations. Sensitivity analyses included MR Egger regression, MR-pleiotropy residual sum and outlier, and Cochran Q-test. In mixed-sex cohorts (Groups 1 and 2), inverse variance weighted results demonstrated significant protective effects: odds ratio (OR) = 0.626, θ = -0.469, P = 2.73 × 10-6 for Group 1 and OR = 0.617, θ = -0.483, P = 3.56 × 10-5 for Group 2. The analyses for male-specific cohorts (Groups 3-10) showed weaker but consistent effects. For Group 3, OR = 0.643, θ = -0.442, P = .010. For Group 4, some instrumental variables associated with confounders were removed. The result became statistically insignificant: OR = 0.680, θ = -0.385, P = .064. For Group 5, the instrument selection criteria were relaxed and significance was retained: OR = 0.695, θ = -0.364, P = .016. For Groups 6 to 10, Bayesian MR was used to strengthen the inferences. In particular, for Group 8, which has a strongly informed prior, a posterior mean θ = -0.358 and a 95% credible interval (-0.575, -0.136) were obtained. This study provides evidence supporting a causal protective effect of later AFS on ED risk. While traditional MR analyses in male-specific cohorts yielded suggestive results, Bayesian MR analyses, which allow for the integration of prior evidence, provided more precise estimates and strengthened the causal inference. These findings may inform future sexual health policies. Strengths include the use of male-specific cohorts and Bayesian enhancement for weak instruments. Limitations include reliance on European-ancestry data and inability to stratify ED subtypes.

Male↗

PubMed2026

Genetically Predicted Muscle Mass and Function in Relation to Deep Vein Thrombosis: A Two-step Mendelian Randomization Study Highlighting the Mediating Role of BMI.

BackgroundSarcopenia is observationally linked to venous thromboembolism, but the causal architecture and underlying biological pathways remain largely unclear. This study investigated the causal effects of sarcopenia-related traits on lower extremity deep vein thrombosis (DVT) and quantified potential mediating mechanisms.MethodsWe performed two-sample bidirectional Mendelian randomization (MR) and two-step mediation MR using large-scale GWAS data from UK Biobank, EMBL-EBI, and FinnGen. Exposures included appendicular lean mass (ALM), leg fat-free mass (LFM), hand grip strength, and walking pace. Eighteen candidate mediators were screened for indirect pathways.ResultsGenetically predicted higher ALM was significantly associated with increased DVT risk (FinnGen: OR = 1.288, 95% CI: 1.215-1.365, P < 0.001). Similar positive associations were observed for LFM (OR = 1.920-1.954, P < 0.001). By contrast, muscle functional traits - grip strength and walking pace - demonstrated no consistent causal effects. Reverse MR confirmed a unidirectional relationship. Body mass index (BMI) emerged as a pivotal mediator, accounting for 7.58% - 10.50% of the ALM-DVT effect and 52.74% - 62.73% of the LFM-DVT effect. Notably, the independent effect of ALM was largely attenuated after adjusting for metabolic confounders in multivariable MR.ConclusionGenetic predisposition to high muscle mass, rather than functional strength, increases DVT risk. This relationship appears to be significantly driven by metabolic adiposity, suggesting that the "muscle-vascular-coagulation" interaction is partly explained by body-size-related metabolic burden. Risk stratification should integrate muscle mass evaluation with comprehensive metabolic health assessments.

Humans↗

PubMed2025

Genetic risk factors in rheumatoid arthritis: A Mendelian randomization study of chronic kidney disease in European populations.

Rheumatoid arthritis (RA) is a heritable autoimmune disease linked to chronic kidney disease (CKD) in observational studies. However, whether this association is causal and driven by shared genetic risk remains unclear, warranting genetic investigation. To investigate possible causal relationships between RA and different CKD subtypes, we used Mendelian randomization (MR) analyses with data from genome-wide association studies. The inverse variance weighted (IVW) methodology was the main method, and sensitivity analyses were added to improve the validity of the causal estimations. Our analysis predicted that RA significantly increases the risk of IgA nephropathy (IVW odds ratio [OR] = 1.041, 95% confidence interval [CI] = 1.018-1.065, P = 4.286e-04), diabetic nephropathy (IVW OR = 1.078, 95% CI = 1.009-1.152, P = .027), nephrotic syndrome (IVW OR = 1.164, 95% CI = 1.078-1.257, P = 1.012e-04), and chronic renal failure (IVW OR = 1.046, 95% CI = 1.018-1.075, P = 1.000e-03). MR analyses confirmed RA's positive causal effect on these CKD subtypes (all P < .05). While heterogeneity was observed for IgA nephropathy and chronic renal failure, sensitivity analyses (MR-Egger intercept, all P > .05) revealed no evidence of horizontal pleiotropy, supporting the robustness of our findings. Our findings suggest that in European-ancestry populations, a genetic predisposition to RA is causally associated with a higher risk of specific types of CKD. While these results require validation in diverse ethnic groups, they highlight the potential importance of renal monitoring for genetically susceptible RA patients, which may help mitigate the public health burden of CKD.

Humans↗

PubMed2026

Hyperthyroidism Is Genetically Associated With Reduced Risk of Parkinson's Disease: A Mendelian Randomization Analysis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose aetiology involves an intricate interplay of genetic, immune, metabolic and environmental factors. Endocrine dysfunction-particularly disturbances of thyroid hormone signalling-has been proposed as a contributor to neurodegeneration, but conventional observational studies have produced inconsistent results, and prior Mendelian randomization (MR) work has largely focused on continuous thyroid biomarkers rather than clinically defined hyperthyroid disease states. To clarify this relationship, we performed a two-sample bidirectional and multivariable MR (MVMR) analysis using large-scale genome-wide association study (GWAS) summary statistics from the FinnGen and IEU Open GWAS databases (European ancestry). Single-nucleotide polymorphisms (SNPs) reaching genome-wide significance (p < 5 × 10-8) for Graves' disease and thyrotoxicosis with diffuse goitre served as instrumental variables. The inverse-variance weighted (IVW) method was the primary analysis, complemented by MR-Egger, weighted median, weighted mode and simple mode estimators, and MVMR adjusted for smoking, alcohol consumption, and body mass index (BMI). In forward analyses, genetically proxied Graves' disease (OR = 0.942, 95% CI 0.901-0.985, p = 0.008) and thyrotoxicosis with diffuse goitre (OR = 0.929, 95% CI 0.879-0.982, p = 0.009) were associated with a lower risk of PD, whereas reverse analyses showed no significant effect of genetic liability to PD on either thyroid trait. The inverse associations remained stable across MVMR models, and sensitivity analyses (Cochran's Q, MR-Egger intercept, MR-PRESSO, leave-one-out) showed no evidence of heterogeneity or horizontal pleiotropy. Collectively, these findings provide genetic evidence consistent with a protective relationship between hyperthyroid disease states and PD, independent of major lifestyle confounders. By focusing on clinically defined hyperthyroid entities rather than continuous thyroid indices, our study complements prior MR work and highlights the thyroid-brain axis-encompassing thyroid hormone signalling and autoimmune-mediated immune modulation-as a biologically plausible and potentially modifiable contributor to PD risk that warrants further mechanistic and translational investigation.

Humans↗

PubMed2026

Exploring the Genetic Link between Irritable Bowel Syndrome and Polycystic Ovary Syndrome: Bidirectional Mendelian Randomization and Machine Learning Approaches.

BACKGROUND: Research has shown a certain correlation between polycystic ovary syndrome (PCOS) and irritable bowel syndrome (IBS). The study aims to determine the directionality and underlying biological processes influencing the relationship between these two disorders. METHODS: We explored the causal relationship between IBS and PCOS by conducting a comprehensive bidirectional Mendelian randomization (MR) analysis using five different methods and conducted robustness assessments. We extracted differentially expressed genes from the IBS and PCOS datasets for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Additionally, we developed a protein-protein interaction (PPI) network and applied the Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) methodologies to pinpoint key diagnostic markers. Diagnostic efficacy was further assessed through Receiver Operating Characteristic (ROC) curve analysis for selected genes. Finally, single-sample gene set enrichment analysis (ssGSEA) was carried out to examine immune cell infiltration in IBS and PCOS. RESULTS: MR analysis identified a causal effect of PCOS on IBS (IVW, OR = 1.034, 95% CI: 1.003-1.065, P = 0.029). Conversely, no relationship between IBS and PCOS was observed in the reverse analysis. Furthermore, integrative bioinformatics and machine learning analyses identified CD14 and CASP1 as key diagnostic biomarkers for both IBS and PCOS, which were significantly associated with immune cell infiltration. CONCLUSION: MR analysis has demonstrated a significant positive causal relationship between PCOS and IBS, though the reverse causality from IBS to PCOS appeared non-significant. The genes CD14 and CASP1 emerged as potential shared diagnostic markers between these two conditions.

Polycystic Ovary Syndrome↗

PubMed2026

Causal determinants of gout in 614,000 adults: A two-sample Mendelian randomization study of dietary, lifestyle, and metabolic traits.

Gout affects over 55 million people worldwide, with prevalence projected to rise by 70% by 2050. Although observational studies have implicated several dietary, lifestyle, and metabolic risk factors, causal relationships remain uncertain because of confounding and reverse causation. Univariable and multivariable two-sample Mendelian randomization (MR) analyses were performed using genome-wide association data from 2 European cohorts: UK Biobank (6543 self-reported gout cases and 456,390 controls) and FinnGen (3576 cases and 147,221 controls). Genetic instruments for 12 exposures, including dried fruit, salad, and cheese intake; smoking initiation; physical activity; body mass index (BMI); and lipid traits, were derived from established genome-wide association study datasets. Inverse-variance weighted regression with multiplicative random effects was the primary analysis, complemented by weighted median, weighted mode, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier, and 3 predefined multivariable models. Benjamini-Hochberg correction was applied across all 24 tests. BMI showed the strongest and most consistent causal effect on gout (FinnGen: odds ratio [OR] = 1.97, 95% confidence interval [CI] = 1.51-2.57; UK Biobank: OR = 1.006, 95% CI = 1.003-1.009; both P < .001) and remained significant in 5 of 6 multivariable models. Triglycerides increased risk in both cohorts (FinnGen: OR = 1.34, 95% CI = 1.08-1.66; UK Biobank: OR = 1.008, 95% CI = 1.004-1.012). These associations survived Benjamini-Hochberg correction, as did high-density lipoprotein cholesterol in UK Biobank (OR = 0.997, 95% CI = 0.994-0.999). Dried fruit intake was inversely associated with gout in FinnGen (OR = 0.34, 95% CI = 0.13-0.92, P = .034) but not in UK Biobank, and did not survive correction for multiple testing. No other exposure reached significance in either cohort. This study provides genetic evidence that BMI is the dominant modifiable causal determinant of gout, with triglycerides contributing independently. Dietary associations were weaker and did not withstand correction for multiple testing, and should be regarded as hypothesis-generating. These findings support prioritizing weight management and metabolic health in gout prevention.

Gout↗

PubMed2026

A bi-directional Mendelian randomization study of sarcopenia-related traits and renal function.

The association between sarcopenia and renal function has been reported in observational studies; however, the directionality and potential causal nature of these associations remain uncertain. We assessed whether genetically predicted sarcopenia-related traits are associated with renal function and vice versa using bidirectional Mendelian randomization (MR). We conducted a bidirectional two-sample MR analysis using publicly available European-ancestry GWAS summary statistics for appendicular lean mass (ALM), hand-grip strength (left and right), and walking pace, and for renal function (cystatin C-based estimated glomerular filtration rate [eGFRcystatin C] and urinary albumin excretion [UAE]). Causal estimates were primarily obtained using inverse-variance weighted (IVW) models, complemented by sensitivity analyses (MR-Egger intercept, weighted median/mode, MR-PRESSO, Radial MR, and leave-one-out). In forward MR, genetically predicted walking pace was positively associated with eGFRcystatin C. Genetically predicted ALM and grip strength (right and left) were inversely associated with UAE. In reverse MR, genetically predicted UAE was inversely associated with ALM and right-hand grip strength. Estimates were broadly consistent across sensitivity analyses, and outlier-robust analyses (MR-PRESSO/Radial MR) yielded similar results. These findings provide genetic evidence consistent with bidirectional relationships between sarcopenia-related traits and renal function (particularly UAE), under standard MR assumptions. Given potential limitations (e.g., heterogeneity, pleiotropy, and possible sample overlap), the results should be interpreted cautiously and complemented by other lines of evidence.

Humans↗

PubMed2026

Cell-type-specific genetic associations in Lewy body dementia identified using single-cell eQTL-based Mendelian randomization.

BACKGROUND: Lewy body dementia (LBD) is a complex neurodegenerative disorder marked by α-synuclein aggregation and dual impairment of cognitive and motor function.While genome-wide association studies have identified risk loci, the cellular mechanisms linking genetic variation to disease susceptibility remain largely unexplored. METHODS: We performed single-cell transcriptome-wide Mendelian randomization using brain cell-type-specific eQTLs across eight major cell types. Genetic associations were evaluated using inverse-variance weighted models, followed by Bayesian colocalization analysis. Replication was performed in independent stratified LBD cohorts based on APOE ε4 carrier status. Phenome-wide association analysis was included as a supplementary, descriptive assessment of cross-trait associations. RESULTS: Expression of ANKRD65 in excitatory neurons was significantly associated with reduced LBD risk (odds ratio = 0.65, 95 % CI: 0.52-0.81, p = 0.00013). This association passed a false discovery rate of 0.1 and showed strong evidence of colocalization (posterior probability = 0.93). Effect direction was consistent across APOE ε4+ and ε4- LBD subgroups in independent cohorts. No genome-wide significant associations were observed with non-neurological traits in the phenome-wide analysis. CONCLUSIONS: Our findings identify a genetically supported, cell-type-resolved association between ANKRD65 expression in excitatory neurons and LBD risk. This study demonstrates the value of integrating cell-resolved transcriptomic regulation with genetic inference to pinpoint functionally relevant targets in neurodegenerative diseases.

Humans↗

PubMed2026

Constipation and Psychiatric Disorders: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies have shown a link between constipation (CN) and psychiatric disorders, including Schizophrenia (SP), Bipolar disorder (BD), Schizoaffective disorder (SD), and Parkinson's disease (PD). However, it is still unknown whether CN affects the occurrence and development of psychiatric disorders or whether psychiatric disorders cause the occurrence and development of CN. Therefore, this study used Mendelian randomization (MR) analysis to evaluate the relationship between CN and psychiatric disorders. METHOD: We used genome-wide association studies (GWAS) to assess the relationship between constipation (N = 411, 623) and four psychiatric disorders, including SP ( N = 77, 096), BD (N = 51, 710), SD ( N = 210, 962), PD (N = 482, 730 ), using bidirectional MR analysis. Inverse variance weighting (IVW), MR Egger (ME) and Weighted median (WM) were used as causal analysis methods. Cochran's Q test, funnel plot, MR Egger intercept test and Leave.one.out analysis were used to detect sensitivity. Confounding factors were analyzed and eliminated by LDtrait to avoid influencing the final MR Analysis result. RESULTS: The results of positive MR analysis indicated that there was no evidence of influence of constipation on SP (OR 1.043, 95%CI 0.946 - 1.149, P value = 0.398), BD (OR 1.114, 95%CI 0.995 - 1.248, P value = 0.062), SD (OR 0.934, 95%CI 0.674 - 1.294, P value = 0.682) and PD (OR 1.118, 95%CI 0.918 - 1.361, P value = 0.269) under gene prediction. Reverse MR analysis suggested that SP (OR 1.030, 95% CI 1.001-1.060, P value = 0.042) had a causal relationship with constipation. BD (OR 0.993, 95% CI 0.962-1.025, P value = 0.664), SD (OR 1.021, 95% CI 0.984-1.059, P value = 0.265) and PD (OR 1.004, 95% CI 0.974-1.035, P value = 0.790) were not associated with CN. CONCLUSION: There was a positive association between SP and CN. CN may have no exact causal relationship with BD, SD and PD, and the interaction mechanism between these diseases needs to be further explored.

Constipation↗

PubMed2025

Assessing the causal effect of genetically predicted metabolites and metabolic pathways on vitiligo: Evidence from Mendelian randomization and animal experiments.

Vitiligo is a common chronic skin depigmentation disorder that seriously decreases the patients' overall quality of life. Human blood metabolites could contribute to unraveling the underlying biological mechanisms of vitiligo. We used GWAS summary statistics to assess the causal association between genetically predicted 1400 serum metabolites and vitiligo risk by Mendelian randomization (MR). Then, after constructing the mouse model of vitiligo, we did non-targeted metabolomics analysis on the mouse serum and validated MR's pathway enrichment results ulteriorly. In the initial phase, MR analysis revealed causative associations between 36 metabolites and vitiligo risk, including 8 metabolite ratios and 28 individual metabolites (19 known and 9 unknown metabolites). In the validation stage, 7 metabolites were successfully validated. Of the 28 individual metabolites, most are related to lipid metabolism. Genetically predicted higher 4-oxo-retinoic acid showed the strongest protective effect on vitiligo, while the most potent risk effect was the increase in quinate. The metabolites associated with vitiligo risk are mainly enriched in alpha-linolenic acid metabolism, linoleic acid metabolism, arginine biosynthesis and metabolism pathways, validated through the serum metabolomics of vitiligo mouse. By integrating genomics and metabolomics, this study provides new insights into the association between metabolites and vitiligo, highlighting the potential roles of specific metabolites in the pathogenesis of vitiligo. These metabolites associated with vitiligo could serve as new biomarkers, further research could help to reveal how these metabolites influence specific pathways in the development of vitiligo.

Animals↗

PubMed2026

The impact for causal associations between common diseases and inflammatory bowel disease: a disease-wide bidirectional Mendelian randomization study.

OBJECTIVES: Observational studies on associations between various diseases and inflammatory bowel disease (IBD) are often limited by confounding and reverse causation. We aimed to assess potential causal relationships between a wide range of diseases and IBD, including Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a comprehensive bidirectional Mendelian randomization (MR) analysis of 104 common diseases and IBD traits using the generalized summary-data-based MR (GSMR) approach. Genome-wide association study (GWAS) summary statistics for diseases were obtained from the MRC Integrative Epidemiology Unit, and IBD data from the International IBD Genetics Consortium. Summary-data-based MR (SMR) integrating GWAS and expression quantitative trait locus data was applied to identify pleiotropic genes associated with IBD. RESULTS: MR analyses identified 38, 34, and 52 exposures significantly associated with IBD, UC, and CD, respectively. Childhood- and adult-onset asthma showed distinct causal effects on UC and CD. Reverse MR indicated associations between IBD traits and 15 diseases, including multiple sclerosis. SMR identified RGS14 and CARD9 as pleiotropic genes linked to IBD, suggesting shared genetic mechanisms with asthma and multiple sclerosis. CONCLUSIONS: These findings provide evidence for causal links and shared immune-related genetic mechanisms underlying IBD, highlighting potential targets for future research.

Humans↗