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Results for “Reverse Mendelian randomization”

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PubMed2025

Education, socioeconomic status, leisure sedentary behaviors and female infertility: mendelian randomization study.

BACKGROUND: Previous studies have indicated that education, socioeconomic status, and leisure sedentary behavior may be associated with female infertility. However, it remains unclear whether these associations imply causal relationships. METHODS: Genetic variants from genome-wide association studies (GWAS) of education, socioeconomic status, and leisure sedentary behaviors were obtained from the UK Biobank and MRC-IEU database (Medical Research Council Integrative Epidemiology Unit), female infertility data was acquired from the FinnGen Biobank. Univariable and multivariable MR analyses were performed to explore the relationships between these traits and female infertility. RESULTS: The results of the univariate MR analysis indicated that age of full-time education had a protective effect on female infertility (odds ratio [OR] 0.471; 95% confidence interval [CI] 0.24 to 0.93; p = 0.03). Multivariable MR and reverse MR studies support the existence of a relationship between them. However, no causal correlation was found between other traits and female infertility. No significant heterogeneity or horizontal pleiotropy was detected, and the stability of the results was confirmed through sensitivity analysis and the leave-one-out test. CONCLUSIONS: A later age of completion of full-time education may be causally related to a reduced risk of female infertility, but no causality is established between other educational levels factors, socioeconomic status, or sedentary behaviors and infertility risk.

Humans↗

PubMed2006

Mendelian randomization: a new approach to studying epidemiology in ESRD.

Associations between environmental exposures and disease in epidemiological studies often are confounded and may result in erroneous interpretations. The random assortment of genes from parents to offspring at gamete formation--Mendelian randomization--is emerging as a useful method for studying the nature (causal or not) of environmental exposures. This occurs because the association between a disease and a polymorphism that mimics the biological link between a given exposure and the same disease is unaffected by the reverse causation that may complicate the interpretation of observational studies. Thus, similarly to randomized trials, association studies between gene polymorphisms with a well-established function may be useful for excluding confounding as an explanation for a given epidemiological relationship. The rationale behind this concept is that transmission of genes occurs in a random way; therefore, offspring have an equal chance of inheriting either of the 2 alleles that their parents have at any particular locus, a phenomenon independent from environmental factors. This is similar to the construct of randomized trials, in which randomization is expected to produce similar distributions of measured and unmeasured confounders between treated and untreated (control) groups. The equivalence between random assortment of alleles and random assignment of interventions in randomized studies is particularly useful because it may give a clue for interpreting associations that may be produced as both the effect of a gene or result of an environmental exposure. Examples are provided about the use of this concept to elucidate paradoxical inverse associations in epidemiological studies in the general and end-stage renal disease populations.

Epidemiologic Research Design↗

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

DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension.

BACKGROUND: Succinylation, a key post-translational modification, is implicated in the metabolic reprogramming and vascular remodeling of pulmonary arterial hypertension (PAH). While epigenetic regulation, particularly DNA methylation, potentially governs succinylation-related gene expression, its causal links to PAH remain unclear. METHODS: We performed an integrative causal analysis using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) to identify succinylation-related genes that influence PAH risk. We leveraged PAH GWAS data (FinnGen) and gene expression quantitative trait loci (eQTLGen). Subsequently, methylation-mediated effect decomposition was applied using DNA methylation data (GoDMC) to explore epigenetic regulation. Experimental validation was conducted in lung tissues from a monocrotaline (MCT)-induced PAH rat model via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Genetic analyses identified a significant causal effect of elevated Transgelin 2 (TAGLN2) expression on increased PAH risk. This effect was mediated by two specific DNA methylation sites, cg13892570 and cg16107628, which influenced PAH pathogenesis by regulating TAGLN2 transcription, with mediation proportions of 86.46 and 97.65%, respectively. Sensitivity analyses supported the robustness of these findings. Consistent with the genetic evidence, TAGLN2 mRNA was significantly upregulated in the lungs of MCT-induced PAH rats. CONCLUSIONS: This study establishes a clear epigenetic causal pathway in which DNA methylation regulates TAGLN2 expression to promote PAH. TAGLN2 is validated as a key disease driver and presents a promising target for diagnostic and therapeutic strategies in PAH.

Animals↗

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

Plasmacytoid dendritic cell-mediated L-glutamate catabolism links gut microbiota to male infertility.

Emerging evidence suggests that gut microbiota composition influences male reproductive health; however, the immunometabolic mechanisms underlying this association remain insufficiently characterized. We investigated whether specific immune cell-mediated metabolic pathways, particularly plasmacytoid dendritic cell (pDC)-driven L-glutamate catabolism via the hydroxyglutarate pathway, contribute to the causal link between gut microbiota and male infertility. We conducted a 2-sample, 2-step Mendelian randomization (MR) analysis using inverse-variance weighting as the primary estimator and Bayesian weighted MR for robustness. Exposure data comprised 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes from large European-ancestry genome-wide association studies. Male infertility genome-wide association studies data (1429 cases; 128,710 controls) were obtained from FinnGen R10. Only exposure-mediator-outcome pairs meeting stringent pleiotropy, heterogeneity, and reverse-causality criteria were retained for mediation analysis. Nine microbial taxa/metabolic pathways and 18 immune traits exhibited putative causal associations with male infertility. The L-glutamate degradation V pathway via hydroxyglutarate was linked to reduced infertility risk (inverse-variance weighting odds ratio [OR] = 0.68; 95% confidence interval, 0.52-0.89; P = .005). Two-step MR suggested that forward scatter area on pDCs may mediate this association, although the mediation effect was imprecise (effect = 0.0277; 95% confidence interval, -0.0348 to 0.0903). This study provides suggestive genetic evidence that pDC-mediated glutamate catabolism may connect gut microbial metabolic activity to male infertility. These findings highlight immunometabolic pathways as testable targets for mechanistic validation and microbiota-directed interventions.

Male↗

PubMed2025

Bioavailable testosterone reduces the risk of lung squamous cell carcinoma: a comprehensive data study.

BACKGROUND: The association between testosterone and lung cancer remains unclear. This study investigates the relationship between testosterone levels and lung cancer risk, focusing on bioavailable testosterone levels (BTLs), total testosterone levels (TTLs), and sex hormone-binding globulin (SHBG) in relation to lung cancer subtypes. METHODS: We utilized bidirectional and multivariable Mendelian randomization (MR) analyses based on genome-wide association studies (GWAS) to assess causal links. To validate the findings clinically, immunohistochemical (IHC) staining for androgen receptor (AR) expression and survival analyses were conducted on a cohort of 90 patients with lung squamous cell carcinoma (LUSC). RESULTS: MR analysis demonstrated that higher BTLs were significantly associated with a reduced risk of LUSC (OR = 0.365, P = 0.001), while no significant associations were observed for TTLs or SHBG. Reverse MR analysis found no causal effect of lung cancer on testosterone levels. Multivariable MR confirmed BTLs as an independent protective factor. In the clinical cohort, AR expression was significantly associated with better prognosis, showing improved median progression-free survival (12.3 vs. 9.0 months, P = 0.01) and median overall survival (35.3 vs. 29.4 months, P < 0.01). Cox regression identified AR expression as an independent protective factor for patient outcomes. However, study limitations include potential residual confounding, ethnic heterogeneity between European GWAS data and Asian clinical cohorts, and the lack of direct experimental validation. CONCLUSIONS: Our findings suggest that higher BTLs may play a protective role against LUSC. BTLs and AR expression show potential as valuable biomarkers for the diagnosis and prognostic assessment of LUSC.

Humans↗

PubMed2024

Effect of inflammatory cytokines and plasma metabolome on OSA: a bidirectional two- sample Mendelian randomization study and mediation analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder. Inflammatory factors and plasma metabolites are important in assessing its progression. However, the causal relationship between them and OSA remains unclear, hampering early clinical diagnosis and treatment decisions. METHODS: We conducted a large-scale study using data from the FinnGen database, with 43,901 cases and 366,484 controls for our discovery MR analysis. We employed 91 plasma proteins from 11 cohorts (totaling 14,824 participants of European descent) as instrumental variables (IVs). Additionally, we conducted a GWAS involving 13,818 cases and 463,035 controls to replicate the MR analysis. We primarily used the IVW method, supplemented by MR Egger, weighted median, simple mode, and weighted mode methods. Meta-analysis was used to synthesize MR findings, followed by tests for heterogeneity, pleiotropy, and sensitivity analysis (LOO). Reverse MR analysis was also performed to explore causal relationships. RESULTS: The meta-analysis showed a correlation between elevated Eotaxin levels and an increased risk of OSA (OR=1.050, 95% CI: 1.008-1.096; p < 0.05). Furthermore, we found that the increased risk of OSA could be attributed to reduced levels of X-11849 and X-24978 (decreases of 7.1% and 8.4%, respectively). Sensitivity analysis results supported the reliability of these findings. CONCLUSIONS: In this study, we uncovered a novel biomarker and identified two previously unknown metabolites strongly linked to OSA. These findings underscore the potential significance of inflammatory factors and metabolites in the genetic underpinnings of OSA development and prognosis.

Female↗

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

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↗

PubMed2026

Shared Genetic Basis, Biological Function and Causal Relationship Between Sleep Traits and Hypothyroidism: Evidence from a Comprehensive Genetic Analysis.

BACKGROUND: This research attempts to clarify whether there are any genetic similarities between sleep traits and hypothyroidism based on publicly accessible large-scale genomewide association studies. METHODS: The methodology included colocalization analysis, cross-phenotype association analysis, and linkage disequilibrium score regression analysis to find common genetic overlap. Through tissue function specificity and functional mapping, we were able to identify the shared genetic level. Genetic instrumental factors were used for causal inference in two-sample univariate and multivariable Mendelian randomization analyses. RESULTS: A hereditary correlation between hypothyroidism and napping during the day and getting up in the morning (rg= -0.0982, P= 0.0007; rg= -0.101, P= 0.0001). MAGI3, and HLA-DRB1 BX296568.1 may be potential targets for shared treatments. Colocalization and tissue-specific analysis demonstrated that the common genes and SNPs were identified in the thyroid, lung, brain, and lymphatic tissues. Functional analysis emphasized the importance of these common genes in processes like as protein transport, inflammatory response, and MHC class II protein synthesis. Furthermore, an association has been established between hypothyroidism and sleep duration (IVW, OR 1.5208; 95% CI 1.1142-2.0758, P=0.0082) and getting up in the morning (IVW, OR 1.8375; 95%CI: 1.4502-2.3284, P=4.73E-07). Furthermore, the reverse MR analysis revealed no causal connection between aberrant sleep traits and hypothyroidism. The enduring impact of insomnia on hypothyroidism persists despite controlling for alcohol consumption and smoking habits. CONCLUSION: Certain genetic correlations between sleep traits and hypothyroidism have been emphasized. These findings may elucidate the origin of comorbidity and have implications for future clinical trials.

Humans↗

PubMed2024

Bidirectional association between abnormal cardiac conditions and epilepsy: A two-sample Mendelian randomization study.

BACKGROUND: Observational studies have consistently indicated a significant correlation between abnormal cardiac conditions and epilepsy. However, the association and direction of this relationship remain a subject of debate. This study employs a two-sample bidirectional Mendelian randomization (MR) approach to investigate the association between abnormal cardiac conditions and epilepsy. METHODS: Instrumental variables, represented by single nucleotide polymorphisms (SNPs) associated with epilepsy and various abnormal cardiac conditions, were derived from large-scale genome-wide association studies databases, including FinnGen and UK Biobank. Bidirectional MR analysis was conducted to estimate the association between epilepsy and abnormal cardiac conditions. Sensitivity analyses were performed using MR-Egger, weighted median, Inverse Variance Weighted, and MR pleiotropy residual sum and outlier methods. RESULTS: The forward MR analysis suggested a potential positive effect of atrial fibrillation and flutter (AF) and valvular heart diseases (VHD) on the risk of epilepsy. Conversely, the reverse MR analysis indicated that epilepsy might increase the susceptibility to AF, VHD, and heart failure. CONCLUSION: The findings support a bidirectional relationship between AF, VHD, and epilepsy, indicating that AF and VHD can elevate the risk of developing epilepsy, while epilepsy, in turn, can also increase the risk of developing AF and VHD. Furthermore, the study suggest that epilepsy may contribute to the development of heart failure. These results underscore the importance of screening for cardiac abnormalities in patients with epilepsy and vice versa, to better understand their clinical significance and potential as modifiable risk factors.

Humans↗

PubMed2026

Causal relationship between asthma and hernia risk: A Mendelian randomization study.

Epidemiological associations between asthma and various hernia subtypes have been reported, but the causality and direction remain unclear. This study employs a two‑sample Mendelian randomization (MR) approach to systematically assess the causal associations between asthma and 6 hernia subtypes. Using publicly available summary data of genome-wide association studies, asthma was selected as the exposure, and diaphragmatic hernia, umbilical hernia, femoral hernia, hiatus hernia, inguinal hernia, and ventral hernia were selected as outcomes. Instrumental variables were strictly screened (F-statistic > 10). The inverse‑variance weighted method was used as the primary analytical approach, supplemented with MR Egger and weighted median methods. Sensitivity analyses included heterogeneity tests, horizontal pleiotropy tests, Steiger directionality tests, leave‑one‑out analyses, and Radial MR. Reverse MR was performed for validation. Forward MR analyses revealed a significant positive causal effect of asthma on diaphragmatic hernia (odds ratio [OR] = 1.19, 95% confidence interval [CI]: 1.08-1.31, P < .001) and a suggestive association with umbilical hernia (OR = 1.19, 95% CI: 1.05-1.34, P = .007). The umbilical hernia association was significant only by the inverse‑variance weighted method; weighted median (P = .102) and MR-Egger (P = .210) estimates were not statistically significant, and the estimate attenuated after outlier removal (confirmatory OR = 1.13, 95% CI: 1.01-1.26, P = .028). Sensitivity analyses showed no significant heterogeneity or pleiotropy. Reverse MR did not identify significant causal effects of hernias on asthma, although power limitations for certain hernia subtypes should be considered. No significant associations were observed between asthma and the other hernia subtypes, although the null findings for femoral and ventral hernias should be interpreted with caution due to limited statistical power. This study provides genetic evidence supporting asthma as a causal risk factor for diaphragmatic hernia, with a suggestive association for umbilical hernia. The diaphragmatic hernia finding was robust across multiple sensitivity analyses, whereas the umbilical hernia association was less consistent and requires further confirmation. These findings contribute to a deeper understanding of the mechanistic links between asthma and specific hernia subtypes.

Mendelian Randomization Analysis↗

PubMed2024

Causal effects of sedentary behaviours on the risk of migraine: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Migraine is a common and burdensome neurological disorder. The causal relationship between sedentary behaviours (SBs) and migraine remains instinct. We aimed to evaluate the roles of SBs including watching TV, using computer and driving in the risk of migraine. METHODS: We conducted a univariable and multivariable Mendelian randomization (MR) study based on summary datasets of large genome-wide association studies. The inverse variance weighted method was utilized as the primary analytical tool. Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier and leave-one-out were conducted as sensitivity analysis. Additionally, we performed a meta-analysis to combine the causal estimates. RESULTS: In the discovery analysis, we identified causal associations between time spent watching TV and an increased risk of migraine (p = 0.015) and migraine without aura (MO) (p = 0.002). Such causalities with increasing risk of migraine (p = 0.005), and MO (p = 0.006) were further verified using summary datasets from another study in the replication analysis. There was no significant causal association found between time spent using computer, driving and migraine or its two subtypes. The meta-analysis and multivariable MR analysis also strongly supported the causal relationships between time spent watching TV and an increased risk of migraine (p = 0.0003 and p = 0.034), as well as MO (p < 0.0001 and p = 0.0004), respectively. These findings were robust under all sensitivity analysis. CONCLUSIONS: Our study suggested that time spent watching TV may be causally associated with an increased risk of migraine, particularly MO. Large-scale and well-designed cohort studies may be warranted for further validation. SIGNIFICANCE STATEMENT: This study represents the first attempt to investigate whether a causal relationship exists between SBs and migraine. Utilizing MR analysis helps mitigate reverse causation bias and confounding factors commonly encountered in observational cohorts, thereby enhancing the robustness of derived causal associations. Our MR analysis revealed that time spent watching TV may serve as a potential risk factor for migraine, particularly MO.

Humans↗

PubMed2026

Systematic Identification of Therapeutic Targets and Repurposed Drugs for Stroke: From Genome Causal Analysis to Multilevel Validation.

BACKGROUND: Stroke is a severe cerebrovascular disease characterized by narrow time windows and complications. This study aimed to identify novel drug targets and repurposed drugs for stroke. METHODS: This study used expression quantitative trait loci data from druggable genes in brain and blood as instrumental variables. Mendelian randomization, colocalization, and phenome-wide Mendelian randomization were applied to evaluate causal relationships and potential side effects, with stroke and ischemic stroke as primary outcomes. Preclinical validation used oxygen-glucose deprivation/reperfusion and middle cerebral artery occlusion/reperfusion models. Pharmacological and behavioral assessments evaluated the therapeutic potential of candidate targets and drugs. Additionally, proteomic sequencing was performed following GGCX (γ-glutamyl carboxylase) overexpression to explore its biological functions. RESULTS: Elevated GGCX expression in brain and blood was potentially causally associated with reduced risk of stroke and ischemic stroke, supported by colocalization evidence, although potential cardiovascular risks could not be excluded. Drug repositioning identified ifenprodil as a candidate agent that reduced infarction volume, improved motor and cognitive functions, and reversed GGCX downregulation in mice. Ifenprodil treatment and GGCX overexpression alleviated oxygen-glucose deprivation/reperfusion-induced injury and upregulated GGCX expression. Mechanistically, GGCX conferred neuroprotection by regulating protein homeostasis, suppressing inflammation, promoting metabolic recovery, and modulating nuclear transcriptional regulation. CONCLUSIONS: This study established a potential causal link between GGCX and stroke risk, particularly ischemic stroke. GGCX represents a promising therapeutic target for ischemic stroke. Targeted GGCX expression upregulation and drug repurposing, particularly ifenprodil, may offer novel therapeutic avenues. Further validation is warranted to assess clinical efficacy and safety.

Animals↗

PubMed2026

Migraine is not a risk factor for glaucoma: Evidence from a bidirectional Mendelian randomization study.

Numerous compelling observational studies have indicated that migraine is a risk factor for the development of glaucoma. Nevertheless, some studies have observed entirely opposite results. The objective of our research is to evaluate the potential relationship between migraine and glaucoma by employing a bidirectional Mendelian Randomization (MR) approach. This method enables us to rigorously assess the causal links between these 2 conditions, thereby addressing the discrepancies in existing literature. Independent genetic variants associated with glaucoma and migraine at the genome-wide significance level were selected as instrumental variables. All summary data were obtained from the genome-wide association study database. The primary method employed in the bidirectional MR analysis was the inverse variance weighted method, while sensitivity analyses utilized the leave-one-out method, MR-Egger method, and MR-Pleiotropy RESidual Sum and Outlier‌ method. When migraine and its subtypes (specifically migraine with aura and migraine without aura) were evaluated as exposure factors, we found no evidence of a causal relationship with glaucoma and its subtypes (namely angle-closure glaucoma and open-angle glaucoma). Subsequently, in the reverse MR analysis, when glaucoma and its subtypes (angle-closure glaucoma and open-angle glaucoma) were assessed as exposure factors, there was no substantial evidence to support a causal relationship with migraine or its subtypes (migraine with aura and migraine without aura). Furthermore, sensitivity analyses also reinforced the robustness of our bidirectional MR findings. Our bidirectional MR analysis mitigates the biases associated with traditional observational studies, highlighting that there is no direct causal relationship between migraine and the risk of glaucoma.

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↗

PubMed2026

Causality between genetically predicted type 2 diabetes and ankle fracture risk: A 2-sample Mendelian randomization study.

It has been proven that diabetes mellitus plays an important role in the occurrence and development of joint fractures. In this study, a 2-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between diabetes and ankle fractures. We pooled the data from the published genome-wide association studies. Diabetes mellitus type 2 was derived from pooled genome-wide association study data of 655,666 European individuals (61,714 patients and 1178 controls). Data on ankle fractures were derived from pooled genome-wide association study data in a total of 460,340 European individuals (6479 patients and 453,861 controls). Using diabetes-associated loci as instrumental variables, we used inverse variance weighting, MR-Egger, weighted median, simple multivariate analysis and weighted multivariate analysis to evaluate the association between diabetes and ankle fracture risk. Reverse MR analysis was performed on the Diabetes mellitus type 2 that were found to be causally associated with ankle fractures in forward MR analysis. Sensitivity analysis was used to evaluate the robustness of the results. Statistical analysis showed a significant causal relationship between diabetes and ankle fractures (inverse variance weighting: OR = 1.07, 95% CI = 1.01-1.32, P = .02). Diabetes mellitus is associated with an increased risk of ankle fracture. The results of MR analysis can be used as a guide for the screening of diabetes and ankle fractures, which is helpful to improve the awareness of screening, early diagnosis and early treatment.

Humans↗