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PubMed2026

Subtype-Specific Causal Effects of C16 and C24 Ceramides on Heart Failure: Evidence From Univariable and Multivariable Mendelian Randomization Analyses.

Ceramides (Cer) are bioactive lipids implicated in cardiovascular disease (CVD), yet their subtype-specific causal effects remain unclear. We performed a two-sample Mendelian randomization (MR) analysis using publicly available GWAS summary statistics to investigate the effects of C16:0-ceramide homologs (Cer16:0) and C24:1-ceramide homologs (Cer24:1) on six CVD outcomes. Instrumental variables were rigorously selected, and multiple MR methods were applied to ensure robust inference. Univariable MR identified a significant inverse association between Cer(d18:1/24:1) and heart failure (HF), which remained significant after false discovery rate correction. In contrast, the association for Cer(d17:1/16:0) did not remain significant after correction. No causal associations were observed for other CVD outcomes. When aggregating subtypes, genetically predicted higher total Cer16:0 levels were associated with increased HF risk, while no significant association was found for total Cer24:1. Multivariable MR further demonstrated that the protective effect of Cer(d18:1/24:1) on HF was robust, while estimates for C16 subtypes were attenuated and sensitive to model specification. In conclusion, our findings support a stable protective role of Cer(d18:1/24:1) in HF and highlight the complexity of subtype-specific effects among structurally related ceramides. These results underscore the importance of considering ceramide heterogeneity in cardiovascular research. Further studies are warranted to validate these findings and explore their clinical implications.

Ceramides↗

PubMed2025

Dietary patterns and risk of ischemic stroke: A two-sample Mendelian randomization study.

Diet and nutrition critically influence the development and outcomes of ischemic stroke (IS). However, observational studies often yield inconsistent findings due to confounding and measurement error. Mendelian randomization (MR) provides an alternative approach to strengthen causal inference. We conducted a 2-sample MR analysis to evaluate the causal associations between 22 dietary factors and IS risk. Genetic instruments for dietary exposures were derived from the UK Biobank genome-wide association study, and outcome data were obtained from the MEGASTROKE consortium. Inverse-variance weighted analysis served as the primary method, complemented by sensitivity analyses. Consumption of oily fish (β = -0.402, P = .022), cheese (β = -0.364, P = .001), dried fruit (β = -0.710, P = .0002), weekly red wine (β = -0.507, P = .024), and calcium supplements (β = -3.994, P = .015) was associated with reduced risk of IS. Conversely, dietary patterns characterized by high-sugar or high-protein intake showed suggestive associations with increased IS risk, although these did not remain significant after multiple-comparison correction. This 2-sample MR study provides evidence that specific dietary factors, including oily fish, cheese, dried fruit, red wine, and calcium, may reduce IS risk, while high-sugar and high-protein diets may confer increased risk. These findings underscore the importance of dietary management in stroke prevention and highlight the need for further studies to validate the role of potentially harmful dietary patterns.

Humans↗

PubMed2026

Multitarget interactions of bisphenol A in polycystic ovary syndrome: evidence from integrated network toxicology, mendelian randomization, and molecular docking.

OBJECTIVE: To study the potential pathogenic mechanisms of bisphenol A (BPA) in polycystic ovary syndrome (PCOS) using an integrative computational strategy. DESIGN: Integrative computational study combining network toxicology, Mendelian randomization (MR), and molecular docking. SUBJECTS: For MR analysis, genetic data were sourced from large European-ancestry cohorts, including plasma protein quantitative trait loci data and genome-wide association study summary statistics for PCOS (3,045 cases and 267,780 controls). EXPOSURE: In silico exposure to BPA for target prediction; genetically predicted plasma protein levels for causal inference. MAIN OUTCOME MEASURES: Identification of overlapping targets between BPA and PCOS; functional enrichment pathways; causal effects of prioritized proteins on PCOS risk (odds ratios with 95% confidence intervals); binding affinities between BPA and core targets (kcal/mol). RESULTS: Network toxicology identified 310 overlapping targets between BPA and PCOS. Enrichment analyses revealed significant involvement in endocrine signaling, inflammatory pathways (eg, IL-17), and cellular processes. MR demonstrated that genetically elevated levels of RET, CXCL8, HTR6, MMP1, MMP9, NTRK1, and TNNI2 were significantly associated with increased PCOS risk, whereas higher PSAP and SHBG levels were protective. Molecular docking confirmed stable binding between BPA and all nine key targets, with strongest affinity for SHBG (-8.4 kcal/mol), followed by NTRK1, TNNI2, and RET. CONCLUSION: This integrative investigation suggests that BPA may contribute to PCOS pathogenesis through multitarget interactions involving inflammatory mediators, endocrine regulators, and tissue remodeling proteins. The findings provide prioritized targets and mechanistic insights for future experimental validation and environmental risk assessment.

Female↗

PubMed2026

Gut Microbiota, Lipidome, and Metabolites Mediate Immune Dysregulation in Diabetic Microvascular Disease: A Two-sample Mendelian Randomization and Mediation Analysis.

INTRODUCTION: Diabetic microvascular disease (DMiVD) involves dysregulated immune cell function, but the precise pathogenic mechanisms remain unclear. MATERIALS AND METHODS: We conducted a two-sample Mendelian randomization (MR) study using comprehensive GWAS and FinnGen summary statistics, encompassing 731 immune cell phenotypes, 473 gut microbial taxa, 91 inflammatory proteins, 179 lipid types, 1,400 plasma metabolites, 20 micronutrients, and DMiVD cases. The analysis aimed to evaluate causal associations between these variables and DMiVD. We further explored potential mediating roles of gut microbiota, plasma lipidome, and metabolites using mediation analysis, with multiple sensitivity tests confirming the robustness of our findings. RESULTS: We identified 20 immune cell phenotypes, 33 gut microbial taxa, 31 lipid types, and 83 plasma metabolites with significant causal associations with DMiVD. Mediation analysis revealed that the risk effect of CD3+ resting Tregs on diabetic nephropathy was partly mediated by phosphatidylcholine (16:0_18:2) (10.7%). Additionally, the protective effect of CX3CR1 on monocytes against DMiVD was partly mediated by Unclassified Bacilli A (35%), Species CAG-177 sp003538135 (22.6%), and triacylglycerol (52:6) (25.5%). DISCUSSION: These findings advance understanding of DMiVD pathogenesis, highlighting that modulation of key metabolic pathways and immune regulatory nodes may represent promising therapeutic strategies. Further experimental studies are needed to validate these potential causal relationships. CONCLUSION: Using causal inference approaches, this study identifies immune cell-mediated mechanisms underlying DMiVD, involving gut microbiota, plasma lipids, and metabolites. The results suggest potential intervention targets for mechanistic studies and therapeutic development.

Mendelian Randomization Analysis↗

PubMed2026

Exploring causal associations between autoimmune diseases and hearing loss: a mendelian randomization study.

OBJECTIVE: The causal relationship between Autoimmune Diseases (ADs) and Hearing Loss (HL) remains unclear. This study investigates whether genetic predispositions associated with ADs contribute to HL risk. METHODS: Mendelian Randomization (MR) analysis was conducted to explore the causal effects of ADs on HL. SNPs from Genome-Wide Association Studies (GWAS) were used as instrumental variables for ADs, including Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (SS), Ankylosing Spondylitis (AS), Multiple Sclerosis (MS), Crohn's Disease (CD), and Ulcerative Colitis (UC). Outcome data included Sensorineural Hearing Loss (SNHL), Conductive Hearing Loss (CHL), Mixed conductive and sensorineural Hearing Loss (MHL), and Sudden Idiopathic Hearing Loss (SIHL). MR analyses employed Inverse Variance Weighted (IVW) as the primary method, supplemented with MR-Egger, weighted median, and weighted mode. Heterogeneity, pleiotropy, and sensitivity were evaluated using Cochran's Q test, MR-Egger regression, MR-PRESSO, and leave-one-out analysis. RESULTS: The IVW method identified nine significant associations: MS-SIHL (OR = 1.0494, 95% CI 1.0072-1.0934), AS-CHL (OR = 1.2832, 95% CI 1.0643-1.5472), AS-MHL (OR = 1.5994, 95% CI 1.3696-1.8678), AS-SNHL (OR = 1.1903, 95% CI 1.1104-1.276), AS-SIHL (OR = 1.481, 95% CI 1.22-1.798), SLE-CHL (OR = 1.0593, 95% CI 1.0116-1.1092), UC-MHL (OR = 1.0907, 95% CI 1.0027-1.1865), CD-CHL (OR = 1.0529, 95%CI: 1.0074-1.1005), and CD-SIHL (OR = 1.0597, 95% CI 1.0177-1.1034). Among these, outliers were detected only in AS-SNHL. After outlier removal, the AS-SNHL association remained significant (OR = 1.1722, p < 0.00001), with resolved heterogeneity and pleiotropy. No heterogeneity and pleiotropy were found for the other associations. CONCLUSION: This study identified nine significant AD-HL associations, emphasizing the need for targeted screening and management of HL in individuals with AD. LEVEL OF EVIDENCE: Level 5.

Humans↗

PubMed2026

Modelling time-varying genetic effects on binary disease risk via functional Mendelian randomization.

MOTIVATION: Genome-wide association studies have identified thousands of genetic variants associated with complex traits, establishing Mendelian randomization (MR) as a powerful framework for causal inference using variants as natural experiments. However, existing MR methods treat causal effects as static, relying on cross-sectional exposure measurements and ignoring how genetic predispositions to disease operate dynamically across the life course. Recovering age-specific causal effect functions from longitudinal data requires combining functional data representations of exposure trajectories with instrumental variable estimation strategies suitable for binary disease endpoints, a methodological gap that has remained unaddressed. RESULTS: We develop a functional MR framework for binary outcomes that integrates functional principal component analysis with two-stage residual inclusion (2SRI), ensuring consistent estimation under the nonlinear logistic link function that renders standard instrumental variable estimators inconsistent. Simulations across different causal effect trajectory shapes, varying measurement densities, and varying instrument strengths demonstrate accurate recovery of time-varying genetically predicted effects with minimal bias. Applied to UK Biobank data, the framework identifies an age-specific causal effect of genetically predicted body mass index on type 2 diabetes risk concentrated in early mid-adulthood and progressively attenuating thereafter. Concordance between the proposed 2SRI estimator applied to type 2 diabetes and the established continuous-outcome functional MR estimator applied to the paired glycated haemoglobin marker in the same cohort provides indirect empirical support for the validity of the proposed approach. AVAILABILITY AND IMPLEMENTATION: The method is implemented in the R package mvfmr, with a full tutorial vignette.

Mendelian Randomization Analysis↗

PubMed2026

A causal relationship between chronic pancreatitis and cardiovascular disease: A two-sample Mendelian randomization analysis.

Current research suggests a link between chronic pancreatitis (CP) and cardiovascular disease (CVD), although the causality remains unclear. The aim of this study was therefore to conduct a 2-sample Mendelian randomization (MR) analysis to determine whether a causal relationship exists between CP and CVD. Summary-level data from publicly available genome-wide association studies of European populations were utilized for the MR analysis. Following quality control measures, independent single-nucleotide polymorphisms associated with CP and CVD were chosen as the genetic instruments. Four complementary MR methods were performed, namely the inverse variance weighted (IVW) method, weighted median, MR-Egger, and leave-one-out sensitivity. The IVW method revealed correlations between alcohol-induced CP and myocardial infarction (odds ratio [OR] = 1.001, 95% confidence interval [CI]: 1.000-1.002, P = .0010), as well as with large artery atherosclerosis stroke (OR = 1.067, 95% CI: 1.030-1.105, P = .0003). The IVW method also suggested that CP was significantly associated with stroke (OR = 1.040, 95% CI: 1.015-1.065, P = .0015) and with ischemic stroke (OR = 1.041, 95% CI: 1.005-1.078, P = .0024). These results remained robust and consistent in the sensitivity analysis. This MR study indicates a significant causal relationship between alcohol-induced CP and elevated risks of myocardial infarction and large artery atherosclerosis stroke, and a causal link between CP and stroke as well as ischemic stroke.

Mendelian Randomization Analysis↗

PubMed2026

Exploring Causal Links Between 91 Circulating Inflammatory Proteins and Hashimoto's Thyroiditis: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Increasing evidence has linked inflammation to Hashimoto's thyroiditis (HT) etiology. However, the causal role of circulating inflammatory proteins in HT remains uncertain. To investigate this, we conducted a bidirectional Mendelian randomization (MR) study. METHODS: Genetic data for 91 inflammatory proteins and HT were sourced from publicly available GWAS databases. The PhenoScanner database was then searched for pleiotropic SNPs associated with potential confounders. Inverse variance weighted (IVW) analysis was used as the primary analysis, simultaneously supplemented by five sensitivity analyses to strengthen the results. RESULTS: The results revealed that, after false discovery rate (FDR) correction, interleukin (IL)-12p40 was causally associated with increased risk of HT (OR [95% CI] = 1.295 [1.172, 1.431], p = 3.66 × 10-7, PFDR = 3.33×10-5). Conversely, none of the inflammatory proteins was a consequence of HT. CONCLUSION: This study suggests that IL-12p40 is probably one of the factors correlated with HT etiology, contributing to a better understanding of the pathogenesis of HT and underscoring the potential for therapeutic interventions targeting inflammatory proteins.

Humans↗

PubMed2026

The bidirectional genetic causality between immunocyte phenotypes and dilated cardiomyopathy: A bidirectional Mendelian randomization study.

The association between immunocyte phenotypes and dilated cardiomyopathy (DCM) has been explored, however the exact pathogenesis of the relationship between immune cells and DCM is unclear. This bidirectional two-sample Mendelian randomization (MR) research aims to further validate the causal link between 731 immunocyte phenotypes and DCM. Summary statistics from a genome-wide association study data of individuals with European ancestry were utilized, including 1444 DCM cases and 353,937 controls, as well as 3757 European adults for the 731 immunocyte phenotypes. Causal effects were estimated using inverse variance weighted, MR-Egger regression, weight median estimator, weighted mode, and simple mode. Sensitivity analysis was conducted to confirm data robustness and feasibility. Based on the inverse variance weighted findings, 14 immunocyte phenotypes were risk factors for DCM (P < .05, odds ratio [OR] > 1), while 15 immunocyte phenotypes exhibited a protective effect on DCM (P < .05, OR < 1). The results of reverse MR analysis suggested evidence that DCM occurrence might elevate the levels of 17 immunocyte phenotypes (P < .05, OR > 1) and decrease the levels of 9 immunocyte phenotypes (P < .05, OR < 1). Our research indicated that CD28 on secreting regulatory T cell could mitigate the occurrence of DCM, and reciprocally, the progression of DCM could reduce the level of CD28 on secreting regulatory T cell. This study confirmed the bidirectional genetic predictive relationship between immunocyte phenotypes and DCM, underscoring the complex interplay between DCM and the immune system.

Cardiomyopathy, Dilated↗

PubMed2025

Dietary antioxidants: a challenge or an opportunity for asthma? Genetic insights from a Two-sample mendelian randomization study.

BACKGROUND: Oxidative stress is crucial in the immune response and airway inflammatory process associated with asthma. While the relationship between dietary antioxidants and asthma remains debated in observational studies, this study uses two-sample Mendelian randomization (MR) to explore a potential causal link. METHODS: We acquired six distinct categories of absolute circulating antioxidants and five different types of metabolic circulating antioxidants from the most recent genome-wide association study data of the European population, including vitamin A (retinol), vitamin C (ascorbic acid), vitamin E (tocopherol), β-carotene, lycopene, and urate. The latest data regarding asthma was obtained from the FinnGen database. We utilized single nucleotide polymorphisms as instrumental variables to conduct five MR methods. To confirm the accuracy of the results, additional sensitivity analyses were performed to eliminate any potential confounding factors, such as heterogeneity and pleiotropy. RESULTS: MR and sensitivity analyses revealed an association between circulating urate and asthma, suggesting a potential increase in asthma risk (OR = 1.090; 95% CI = 1.030-1.150; p = 0.004). No causal relationship was found for other antioxidants. CONCLUSIONS: This MR analysis suggested that genetically determined circulating urate may increase asthma risk. Further large-scale randomized controlled trials and mediated MR analysis are needed to explore underlying mechanisms.

Humans↗

PubMed2026

Investigating the causal role of smoking in gout: A triangulation approach combining NHANES data, genetic correlation, and Mendelian randomization.

The relationship between smoking and the development of gout is not well understood. To address this, we adopted a triangulation framework that integrates observational analysis, genetic correlation estimation, and two-sample Mendelian randomization (MR) to examine whether smoking confers a causal risk for gout. We first performed a cross-sectional analysis using information for 13,626 participants from the National Health and Nutrition Examination Survey between 2013 and 2018. The association of smoking with gout was subsequently assessed through logistic regression models. We next investigated the extent of shared genetic factors between smoking phenotypes and gout. We were able to demonstrate this using the linkage disequilibrium score regression applied to genome-wide association study data of European ancestry. Finally, to verify the causality of our relationship, we carried out a two-sample MR analysis. We selected the inverse-variance weighted (IVW) method and confirmed the consistency of using the IVW method with other statistical methods, including weighted median, weighted mode, and simple mode, as well as MR-Egger regression. We performed sensitivity analyses to investigate the heterogeneity of the hypothesis and stability of the data. Our findings based on National Health and Nutrition Examination Survey data reveal that there is a strong positive association between smoking and the risk of gout (odds ratio [OR] = 1.94, 95% confidence interval [CI] = 1.48-2.55, P < .001). This association persisted after confounding adjustments (OR = 1.41, 95% CI = 1.04-1.91, P = .027). In the subgroup analyses, former smokers and current smokers of 10 to 20 cigarettes per day had a substantially increased risk. Post-linkage disequilibrium score regression analysis revealed that the significantly positive genetic correlations of smoking initiation and lifetime smoking index with gout risk were both significantly positive. Additional evidence for causality is presented by MR. Genetic prediction of smoking initiation statistically increases gout risk (IVW OR = 1.55, 95% CI = 1.26-1.90, P = 3.17 × 10-5). A much stronger association is evident for lifetime smoking index (IVW OR = 1.99, 95% CI = 1.44-2.76, P = 3.24 × 10-5). These findings are the same with or without heterogeneity by sensitivity analysis. In light of our integrated analysis, smoking is a causative factor for gout. This suggests that public health interventions like anti-smoking campaigns might reduce gout incidence.

Humans↗

PubMed2025

Association Between Ratio of Triglycerides to HDL-C and Cognitive Impairment: A Longitudinal Population-Based Analysis and Mendelian Randomization Study.

OBJECTIVES: This study aimed to explore the longitudinal association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and cognitive impairment in older adults and further assess potential causality using Mendelian randomization (MR). DESIGN: Longitudinal population-based analysis combined with two-sample MR. Data from Waves 6-8 (2015-2019) of the Survey of Health, Ageing, and Retirement in Europe (SHARE) were analyzed using hierarchical regression models and mixed linear effects models. MR utilized genome-wide association studies (GWAS) summary data. PARTICIPANTS: 11,444 adults aged ≥60 years from SHARE Wave 6, with longitudinal follow-up in Waves 7 (N = 2,775) and 8 (N = 5,469). MEASUREMENTS: TG/HDL-C ratio, cognitive function (orientation, immediate/delayed recall, verbal fluency, numeracy), and cognitive impairment (defined as scores >1.5 SD below age-group mean). Covariates included socio-demographics, health behaviors, comorbidities, and national-level factors. MR employed genetic variants associated with TG/HDL-C as instrumental variables. RESULTS: Higher TG/HDL-C ratios were negatively associated with total cognitive scores (β = -0.115, χ² = 15.44, df = 1, p < 0.001), immediate recall (β = -0.029, χ² = 12.34, df = 1, p < 0.001), delayed recall (β = -0.028, χ² = 7.33, df = 1, p < 0.001), verbal fluency (β = -0.038, χ² = 11.53, df = 1, p < 0.001), and numeracy (β = -0.019, χ² = 4.55, df = 1, p < 0.05) in fully adjusted models. Longitudinal analysis revealed increased cognitive impairment risk in the highest TG/HDL-C quartile (OR=1.43, 95% CI:1.01-2.03, χ² = 9.24, df = 1) over 4 years. MR supported a causal link between elevated TG/HDL-C and cognitive decline. CONCLUSIONS: Elevated TG/HDL-C ratios are longitudinally associated with cognitive decline in older adults. Managing lipid metabolism may mitigate cognitive impairment, highlighting the importance of TG/HDL-C as a modifiable risk factor in aging populations.

Humans↗

PubMed2026

Causal effects of cholelithiasis on hepatopancreatobiliary diseases: a multi-cohort Mendelian randomization study.

BACKGROUND: Cholelithiasis is commonly associated with multiple hepatopancreatobiliary diseases, yet whether these relationships reflect causal mechanisms or shared risk factors remains unclear. METHODS: We performed a phenome-oriented two-sample Mendelian randomization (MR) analysis to evaluate the causal impact of genetic liability to cholelithiasis across hepatopancreatobiliary outcomes. Independent genome-wide significant variants were selected as instrumental variables. Primary analyses used inverse variance weighting, complemented by sensitivity analyses, reverse MR, and multivariable MR adjusting for body mass index (BMI). RESULTS: Genetic predisposition to cholelithiasis was associated with increased risk of acute pancreatitis and extrahepatic cholangiocarcinoma (eCCA), with consistent directionality across datasets.The association with acute pancreatitis was interpreted as a positive control, whereas the null association with alcohol-induced acute pancreatitis served as a negative control. No causal association was observed for portal vein thrombosis. Sensitivity analyses, including MR-PRESSO and MR Steiger filtering, supported the robustness and directionality of the causal estimates. Reverse MR analyses showed no consistent evidence supporting reverse causality. Multivariable MR indicated that observed effects were not fully explained by BMI-related pathways. CONCLUSION: These findings suggest that cholelithiasis susceptibility may contribute to the broader hepatopancreatobiliary disease network, extending its clinical relevance beyond a localized biliary disorder.

Mendelian Randomization Analysis↗

PubMed2025

Immunosuppressant use may be a potential mediator in the progression of systemic lupus erythematosus to osteomyelitis: A bidirectional Mendelian randomization study.

The prevalence of osteomyelitis (OM) is elevated in patients with systemic lupus erythematosus (SLE), but the causal direction and proportion of immunosuppressant (IS) use in this relationship is unclear. Therefore, this study used a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between SLE and OM and to quantify the role of IS use as a potential mediator. Genome-wide association study summary-level data were used to obtain genetic instrumental variables for SLE (5201 cases and 9066 controls), OM (1881 cases and 391,037 controls), and IS (3954 cases and 268,648 controls) genetic instrumental variables with no overlap between their participant populations. Causal and total effects of SLE and OM were analyzed using bidirectional MR. Subsequent "2-step" MR was used to assess the direct effect between the 2 and the indirect effect of IS. Inverse variance weighting was used as the primary method of MR, while a series of sensitivity analyses were performed to assess the reliability of the results. Forward MR of inverse variance weighting results demonstrated a positive causal association between SLE and OM (P = .003, odds ratio [OR] = 1.062, 95% confidence interval [Cl]-OR: 1.019-1.107). The reverse MR results indicated no causal effect of OM on SLE was found (P = .503, OR = 0.914, 95% Cl-OR: 0.703-1.188). The direct effect of SLE acting on OM in our study was found to be 19.36% by 2-step analysis, and the indirect effect of OM through IS was found to be 68.11% (proportion mediated: 68.11%; 95% CI = 0.2277331-1.134507). There was no heterogeneity in all MR analyses of causality, except for the MR analysis of SLE causally related to IS. Sensitivity analysis found no evidence of horizontal pleiotropy. The present study found an increased relative risk of OM in SLE. Mediation analysis suggested a potential substantial mediating role for IS; however, this estimate was highly imprecise and requires further validation. In clinical practice, clinicians should remain aware of the potential for IS therapy to influence infection risk, including OM, in SLE patients.

Humans↗

PubMed2025

Identifying novel protein biomarkers with cross-psychiatric disorders effects and potential intervention targets: Evidence from proteomic-Mendelian randomization.

Plasma proteins are the potential therapeutic targets for psychiatric disorders due to their important roles in signal transduction. We aimed to explore the plasma protein biomarkers with cross-psychiatric disorders effects. Proteome-wide Mendelian randomization (MR) and colocalization analyses were performed to investigate the potential causal relationship between plasma protein biomarkers and 12 psychiatric disorders and further identify the potential proteins with cross-effects. To assess the directionality and exclude potential reverse causation, Steiger directionality tests and reverse MR analyses were additionally conducted. Then, validation analysis was performed by employing summary data from cross-psychiatric disorder GWAS to validate the cross-psychiatric effects of proteins. Protein-protein interactions were conducted to evaluate the interaction between candidate proteins and druggability assessment was used to prioritize potential drug targets for psychiatric disorders. We identified novel plasma proteins that possessed cross-psychiatric disorder effects, especially BTN2A1 and BTN3A2 associated with major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BIP); ITIH1, ITIH3, ITIH4 and FES associated with SCZ and BIP, and the cross-effects of these proteins on SCZ and BIP were confirmed by validation analyses. Steiger tests and reverse MR supported causal directionality. Besides, the protein-protein interactions (PPI) analysis indicated cross-effects proteins had significant interaction, especially ITIH1-ITIH3. The druggability assessment prioritized eight proteins, two of which (ITIH3 and NCAM1) has been targeted by antipsychotic drugs. Our findings provided insights into shared biological mechanisms underlying these conditions.

Humans↗

PubMed2026

Genetic Association Between Sleep Traits and Vertigo Risk: A Two-sample Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies suggest the potential association between sleep traits and vertigo; however, causal evidence remains limited. OBJECTIVE: This study aimed to explore the relationship between genetically predicted sleep traits and vertigo with the Mendelian randomization (MR) method. METHODS: Instrumental variables for sleep traits (snoring, sleep duration, insomnia, daytime sleepiness, daytime napping, and chronotype) were adopted from genomewide association studies (GWAS) data of European ancestry from UK Biobank. The summary-level datasets of vertigo were retrieved from the GWAS of FinnGen. Inversevariance weighted (IVW) method was adopted as the main analysis. RESULTS: IVW analysis revealed a significant association between genetically predicted daytime napping (OR = 1.51, 95% CI =1.08-2.12, P = 0.016) and chronotype (OR = 1.13, 95% CI =1.01-1.26, P = 0.033), both of which were associated with an increased risk of vertigo. However, we did not find evidence for a causal effect of snoring, overall sleep duration, long sleep duration, short sleep duration, insomnia, and excessive daytime sleepiness on vertigo. No reverse causality was detected. CONCLUSION: Our findings suggest that abnormal sleep patterns may serve as risk factors for vertigo disorders and offer opportunities for the prevention and management of vertigo disorders.

Humans↗

PubMed2026

Integrative Multi-Omics Mendelian Randomization Analysis Identifies NIT2 as a Potential Metabolic Risk Gene in Hepatocellular Carcinoma.

BACKGROUND: Metabolic pathways are crucial in hepatocellular carcinoma (HCC) pathogenesis, but causal metabolic genes remain unclear. This study used Summary data-based Mendelian Randomization (SMR) and colocalization to identify metabolism-related genetic loci influencing HCC risk. METHODS: Differentially expressed genes in hepatic malignancy phenotype versus normal tissues from TCGA and GTEx were analyzed. Metabolism-related candidates were examined via SMR and colocalization using multi-omics data: methylation (mQTL), expression (eQTL), and protein (pQTL) quantitative trait loci. RESULTS: Multi-omics integration identified NIT2 as a key metabolic regulator for HCC. The cg13016775 locus of NIT2 was associated with elevated HCC risk at gene (OR = 1.618, 95% CI: 1.199-2.182) and protein (OR = 4.432, 95% CI: 1.783-11.018) levels. Colocalization supported a shared causal variant (PPH4 > 0.6), linking NIT2 to hepatocarcinogenesis via metabolic regulation. CONCLUSIONS: This study provides multi-omics evidence for NIT2 as a potential causal gene in HCC, enhancing understanding of metabolic contributions to HCC pathogenesis and highlighting integrative genomics for uncovering causal relationships.

Carcinoma, Hepatocellular↗

PubMed2026

Causality between noise pollution and Alzheimer disease: A Mendelian randomization analysis.

The role of noise pollution as a risk factor for Alzheimer disease (AD) is unclear, with observational studies yielding conflicting results susceptible to confounding and reverse causality. To clarify this relationship, we performed a 2-sample Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies of European populations. Genetically predicted daytime and evening noise exposure was used as an instrumental variable to assess a causal effect on AD risk. The primary analysis was conducted using the inverse-variance weighted method, with weighted median and MR-Egger methods as key sensitivity analyses. We assessed instrument validity and pleiotropy using the Cochran Q test, the MR-Egger intercept, and leave-one-out analysis. Our MR analysis found no evidence of a causal association between genetically predicted daytime noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.006], P = .819) or evening noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.005], P = .643) and the risk of AD. Sensitivity analyses were consistent, with no evidence of heterogeneity or directional pleiotropy. In conclusion, this study does not support a direct causal link between noise and AD. While our findings mitigate common observational biases, they do not preclude indirect mechanisms whereby noise may influence AD pathogenesis via established risk pathways, such as chronic sleep disruption and cardiovascular stress. Studies are needed to focus on disentangling these potential indirect effects.

Alzheimer Disease↗