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Previous observational studies have reported inconsistent associations between nut consumption and cardiovascular diseases (CVD). This study aims to identify the causal relationship between different types of nuts consumption and CVD, and to quantify the potential mediating effects of cardiometabolic factors. We utilized Genome-Wide Association Study (GWAS) data to assess the causal effects of nut consumption on CVD using two-sample Mendelian randomization (MR) and a two-step MR analysis. The inverse variance weighted (IVW) method indicated that processed (salted or roasted) peanuts were potentially and positively associated with ischaemic heart disease (IHD) (OR 1.4866; 95%CI 1.0491-2.1065). No causal relationships were found between nuts consumption and other CVD outcomes, including atrial fibrillation, angina, coronary atherosclerosis, coronary heart disease, IHD, myocardial infarction, subarachnoid hemorrhage, intracerebral haemorrhage and stroke. Both MR-Egger and median-based methods yielded similar results to IVW. Furthermore, in the two-step MR analysis, fasting insulin, low-density lipoprotein cholesterol and fasting blood glucose were identified as mediators in the potential causal relationship between processed peanuts and IHD, explaining 16.98%, 6.38% and 4.91% of the mediation, respectively. In total, these mediators accounted for 28.27% of the association between salted or roasted peanuts and IHD. [ABSTRACT FROM AUTHOR]

Abstract Urolithiasis is a common and recurrent condition in the urological spectrum. Despite various proposed mechanisms, the causal relationship between sleep traits and the risk of urolithiasis remains unclear. We used publicly available genome-wide association study (GWAS) summary data from the UK Biobank and FinnGen to perform a two-sample Mendelian randomization (MR) analysis and genetic correlation analysis, evaluating the causal relationship and genetic correlation between sleep traits (chronotype, getting up in the morning, sleep duration, nap during the day, and insomnia) and urolithiasis (calculus of the kidney and ureter, and calculus of the lower urinary tract). Additionally, multivariable MR (MVMR) analysis adjusted for body mass index (BMI) and other sleep characteristics was conducted to assess the direct impact of sleep traits on the risk of urinary tract stones. The LD score regression (LDSC) analysis indicated a genetic correlation between insomnia and upper urinary tract stones (rg = 0.082, P = 0.017, Adjusted P = 0.085), but no significant genetic correlation was found for other sleep traits. Our results indicated no causal relationship between sleep traits and upper urinary tract stones. However, insomnia was significantly associated with a higher risk of lower urinary tract stones (IVW [inverse variance weighted] OR [odds ratio] = 5.91, 95% CI [confidence interval] 1.52–22.98, P = 0.010, Adjusted P = 0.030), while early rising exhibited a protective effect (IVW OR = 0.29, 95% CI 0.11–0.76, P = 0.012, Adjusted P = 0.030). In the MVMR analysis, insomnia consistently showed a similar trend, whereas daytime napping significantly reduced the risk of lower urinary tract stones (OR = 0.28, 95% CI 0.12–0.65, P = 0.003). This study provides MR-based evidence suggesting that insomnia may increase the risk of lower urinary tract stones, while daytime napping may reduce this risk. No causal relationship was found between sleep characteristics and upper urinary tract stones.

Abstract Hearing loss(HL) represents a significant public health concern. This study aimed to determine the association between hearing loss and gout and to elucidate the underlying causative mechanisms. Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES) and Mendelian randomization (MR) basic databases. Initially, baseline characteristics of individuals with and without gout were compared. A nonlinear relationship between pure tone audiometry (PTA) values and gout prevalence was confirmed through restricted cubic spline (RCS) curve analysis. Subsequently, hearing loss was categorized into different levels based on PTA values, and multiple logistic regression analysis was employed to calculate the impact of varying degrees of hearing loss on the risk of gout. Finally, MR analysis was conducted to further elucidate the causal relationship between hearing loss and gout. A total of 3,258 individuals were included in this study, with a gout prevalence of 3.7%. Significant differences were observed between the gout group and the non-gout group in variables such as age, gender, blood uric acid level, BMI, hypertension, and diabetes. RCS curve analysis revealed a significant nonlinear relationship between PTA values and gout risk, particularly when PTA values exceed a specific threshold, where the curve flattens. Based on different levels of hearing loss derived from PTA values, multiple logistic regression analysis demonstrated that mild and moderate hearing loss significantly increased the risk of gout, remaining statistically significant after adjusting for covariates (odds ratio (OR) = 2.10–3.48, P

Abstract Objective Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. Method Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. Result Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. Conclusion The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

Abstract Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD.

Abstract While numerous studies have underscored the implication of immune cells and metabolites in temporomandibular disorders (TMD), conclusive evidence for causality remains elusive. Consequently, our aim is to explore the causal connections between immunophenotypes and plasma metabolites in relation to TMD employing a bidirectional Mendelian randomization (MR) approach. Summary statistics data on 731 immunophenotypes (n = 3757) and 1091 plasma metabolites (n = 8299) were obtained from comprehensive genome-wide association studies (GWAS), while TMD data (5668 cases and 205,355 controls) were acquired from the FinnGen Consortium. Bidirectional MR analyses and a two-step MR approach assessed causal relationships and potential intermediaries. Various corrections and sensitivity analyses were utilized to assess the robustness of the findings. Two immunophenotypes and seven metabolites were significantly associated with TMD risk. Specifically, Alpha-hydroxyisovalerate mediated the link between CD33 on CD33dim HLA DR + CD11b + and TMD (β = 0.034, P = 5.95 × 10–5), while CD8 on NKT cells mediated the causal relationship between 5-acetylamino-6-formylamino-3-methyluracil levels and TMD (β = 0.069, P = 5.11 × 10–5). Our findings revealed the causal relationships between immunophenotypes and plasma metabolites on TMD from a genetic perspective, potentially aiding in TMD prevention.

Hearing loss(HL) represents a significant public health concern. This study aimed to determine the association between hearing loss and gout and to elucidate the underlying causative mechanisms. Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES) and Mendelian randomization (MR) basic databases. Initially, baseline characteristics of individuals with and without gout were compared. A nonlinear relationship between pure tone audiometry (PTA) values and gout prevalence was confirmed through restricted cubic spline (RCS) curve analysis. Subsequently, hearing loss was categorized into different levels based on PTA values, and multiple logistic regression analysis was employed to calculate the impact of varying degrees of hearing loss on the risk of gout. Finally, MR analysis was conducted to further elucidate the causal relationship between hearing loss and gout. A total of 3,258 individuals were included in this study, with a gout prevalence of 3.7%. Significant differences were observed between the gout group and the non-gout group in variables such as age, gender, blood uric acid level, BMI, hypertension, and diabetes. RCS curve analysis revealed a significant nonlinear relationship between PTA values and gout risk, particularly when PTA values exceed a specific threshold, where the curve flattens. Based on different levels of hearing loss derived from PTA values, multiple logistic regression analysis demonstrated that mild and moderate hearing loss significantly increased the risk of gout, remaining statistically significant after adjusting for covariates (odds ratio (OR) = 2.10–3.48, P < 0.05). MR analysis further confirmed the causal relationship between hearing loss and gout. Inverse variance weighting (IVW) was employed as the primary method, revealing that both individuals with hearing difficulties (OR = 0.98, 95% confidence interval (CI) 0.96–0.999, P = 0.012) and those without hearing impairment (OR = 1.02, 95% CI 1.01–1.04, P = 0.012) exhibited a significant causal relationship with gout. Goodness-of-fit tests and sensitivity analyses were used to verify the reliability of the results. Hearing loss has a significant causal relationship with an increased risk of gout, providing a new perspective for the prevention and management of gout. Focused attention and prompt treatment of hearing loss, particularly mild and moderate hearing loss, may significantly reduce the risk of developing gout. [ABSTRACT FROM AUTHOR]

Objective: Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. Method: Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. Result: Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. Conclusion: The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN. [ABSTRACT FROM AUTHOR]

While numerous studies have underscored the implication of immune cells and metabolites in temporomandibular disorders (TMD), conclusive evidence for causality remains elusive. Consequently, our aim is to explore the causal connections between immunophenotypes and plasma metabolites in relation to TMD employing a bidirectional Mendelian randomization (MR) approach. Summary statistics data on 731 immunophenotypes (n = 3757) and 1091 plasma metabolites (n = 8299) were obtained from comprehensive genome-wide association studies (GWAS), while TMD data (5668 cases and 205,355 controls) were acquired from the FinnGen Consortium. Bidirectional MR analyses and a two-step MR approach assessed causal relationships and potential intermediaries. Various corrections and sensitivity analyses were utilized to assess the robustness of the findings. Two immunophenotypes and seven metabolites were significantly associated with TMD risk. Specifically, Alpha-hydroxyisovalerate mediated the link between CD33 on CD33dim HLA DR + CD11b + and TMD (β = 0.034, P = 5.95 × 10–5), while CD8 on NKT cells mediated the causal relationship between 5-acetylamino-6-formylamino-3-methyluracil levels and TMD (β = 0.069, P = 5.11 × 10–5). Our findings revealed the causal relationships between immunophenotypes and plasma metabolites on TMD from a genetic perspective, potentially aiding in TMD prevention. [ABSTRACT FROM AUTHOR]

Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD. [ABSTRACT FROM AUTHOR]

Abstract Aging is a recognized risk factor for periodontitis, while biological aging could provide more accurate insights into an individual's functional status. This study aimed to investigate the potential association between biological aging and periodontitis. Epidemiological data from 9803 participants in the 2009–2014 National Health and Nutrition Examination Survey were analyzed at a cross-sectional level to assess this link. Three biological ages [Klemera–Doubal method (KDM), PhenoAge, and homeostatic dysregulation (HD)] and two measures of accelerated biological aging (BioAgeAccel and PhenoAgeAccel) were set as primary exposure and were calculated. Logistic regression and restricted cubic spline regression were employed to examine the relationship between biological aging and periodontitis. Additionally, Mendelian randomization analysis was conducted to explore the causal connection between accelerated biological aging and periodontitis. After adjusting for age, gender, race, educational level, marital status, ratio of family income, and disease conditions, this study, found a significant association between subjects with older higher biological ages, accelerated biological aging, and periodontitis. Specifically, for a per year increase in the three biological ages (HD, KDM, and PhenoAge), the risk of periodontitis increases by 15%, 3%, and 4% respectively. Individuals who had positive BioAgeAccel or PhenoAgeAccel were 20% or 37% more likely to develop periodontitis compared with those who had negative BioAgeAccel or PhenoAgeAccel. Furthermore, a significant non-linear positive relationship was observed between the three biological ages, accelerated biological aging, and periodontitis. However, the Mendelian randomization analysis indicated no causal effect of accelerated biological aging on periodontitis. Our findings suggest that biological aging may contribute to the risk of periodontitis, highlighting the potential utility of preventive strategies targeting aging-related pathways in reducing periodontitis risk among older adults.

Abstract Body mass index (BMI) is a crucial health indicator for obesity. With the progression of socio-economic status and alterations in lifestyle, an increasing number of global populations are at risk of obesity. Given the complexity and severity of neurological diseases, early identification of risk factors is vital for the diagnosis and prognosis of such diseases. In this study, we employed Mendelian randomization (MR) analysis utilizing the most comprehensive genome-wide association study (GWAS) data to date. We selected single nucleotide polymorphisms (SNPs) that are unaffected by confounding factors and reverse causality as instrumental variables. These variables were used to evaluate the genetic and causal relationships between Body Mass Index (BMI) and various neurological diseases, including Parkinson’s Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Ischemic Stroke (IS), and Epilepsy (EP). The Inverse Variance Weighted (IVW) analysis indicated that there was no significant causal relationship between Body Mass Index (BMI) indicators and PD (P-value = 0.511), AD (P-value = 0.076), ALS (P-value = 0.641), EP (P-value = 0.380). However, a causal relationship was found between BMI indicators and MS (P-value = 0.035), and IS (P-value = 0.000), with the BMI index positively correlated with the risk of both diseases. The Cochran’s Q test for MR-IVW showed no heterogeneity in the MR analysis results between the BMI index and the neurological diseases (P > 0.05). The Egger intercept test for pleiotropy revealed no horizontal pleiotropy detected in any of the neurological diseases studied (P > 0.05). It was found that there was no causal relationship between BMI and PD, AD, ALS, EP, and a genetic causal association with MS, and IS. Meanwhile, the increase in BMI can lead to a higher risk of MS and IS, which reveals the critical role of obesity as a risk factor for specific neurological diseases in the pathogenesis of the diseases.

Aging is a recognized risk factor for periodontitis, while biological aging could provide more accurate insights into an individual's functional status. This study aimed to investigate the potential association between biological aging and periodontitis. Epidemiological data from 9803 participants in the 2009–2014 National Health and Nutrition Examination Survey were analyzed at a cross-sectional level to assess this link. Three biological ages [Klemera–Doubal method (KDM), PhenoAge, and homeostatic dysregulation (HD)] and two measures of accelerated biological aging (BioAgeAccel and PhenoAgeAccel) were set as primary exposure and were calculated. Logistic regression and restricted cubic spline regression were employed to examine the relationship between biological aging and periodontitis. Additionally, Mendelian randomization analysis was conducted to explore the causal connection between accelerated biological aging and periodontitis. After adjusting for age, gender, race, educational level, marital status, ratio of family income, and disease conditions, this study, found a significant association between subjects with older higher biological ages, accelerated biological aging, and periodontitis. Specifically, for a per year increase in the three biological ages (HD, KDM, and PhenoAge), the risk of periodontitis increases by 15%, 3%, and 4% respectively. Individuals who had positive BioAgeAccel or PhenoAgeAccel were 20% or 37% more likely to develop periodontitis compared with those who had negative BioAgeAccel or PhenoAgeAccel. Furthermore, a significant non-linear positive relationship was observed between the three biological ages, accelerated biological aging, and periodontitis. However, the Mendelian randomization analysis indicated no causal effect of accelerated biological aging on periodontitis. Our findings suggest that biological aging may contribute to the risk of periodontitis, highlighting the potential utility of preventive strategies targeting aging-related pathways in reducing periodontitis risk among older adults. [ABSTRACT FROM AUTHOR]

Body mass index (BMI) is a crucial health indicator for obesity. With the progression of socio-economic status and alterations in lifestyle, an increasing number of global populations are at risk of obesity. Given the complexity and severity of neurological diseases, early identification of risk factors is vital for the diagnosis and prognosis of such diseases. In this study, we employed Mendelian randomization (MR) analysis utilizing the most comprehensive genome-wide association study (GWAS) data to date. We selected single nucleotide polymorphisms (SNPs) that are unaffected by confounding factors and reverse causality as instrumental variables. These variables were used to evaluate the genetic and causal relationships between Body Mass Index (BMI) and various neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Ischemic Stroke (IS), and Epilepsy (EP). The Inverse Variance Weighted (IVW) analysis indicated that there was no significant causal relationship between Body Mass Index (BMI) indicators and PD (P-value = 0.511), AD (P-value = 0.076), ALS (P-value = 0.641), EP (P-value = 0.380). However, a causal relationship was found between BMI indicators and MS (P-value = 0.035), and IS (P-value = 0.000), with the BMI index positively correlated with the risk of both diseases. The Cochran's Q test for MR-IVW showed no heterogeneity in the MR analysis results between the BMI index and the neurological diseases (P > 0.05). The Egger intercept test for pleiotropy revealed no horizontal pleiotropy detected in any of the neurological diseases studied (P > 0.05). It was found that there was no causal relationship between BMI and PD, AD, ALS, EP, and a genetic causal association with MS, and IS. Meanwhile, the increase in BMI can lead to a higher risk of MS and IS, which reveals the critical role of obesity as a risk factor for specific neurological diseases in the pathogenesis of the diseases. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10-3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [ORSD] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (ORSD = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma.

Age-related macular degeneration (AMD) is a complex multifactorial disease with a significant genetic component. Despite extensive research efforts, the underlying molecular mechanisms remain elusive, necessitating innovative approaches to identify specific genes involved in the pathogenesis of AMD and to elucidate their functional mechanisms. A transcriptome-wide association study (TWAS) was conducted by integrating eQTL data from 49 tissues of the Genotype-Tissue Expression Project (GTEx) v8 and AMD data from FinnGen R10. The Unified Test for Molecular Signatures (UTMOST) and Functional Summary-based Imputation (FUSION) were used to evaluate gene associations with AMD across tissues and within individual tissues, respectively. Multi-marker Analysis of Genomic Annotation (MAGMA) was employed to validate results and identify reliable susceptibility genes, followed by summary data-based Mendelian randomization (SMR) and colocalization analyses to explore causal associations. The cross-tissue and single-tissue TWAS analyses identified 12 reliable AMD-associated genes. MAGMA analysis confirmed 6 of these as reliable susceptibility genes. SMR analysis provided further validation of these genes, although colocalization results were not significant. This study identified six susceptibility genes associated with the risk of AMD through a cross-tissue TWAS, providing new insights into the potential systemic regulatory mechanisms underlying AMD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Prostate cancer (PCa) is a common form of malignancy among men. The associations between socioeconomic status (SES) indicators and PCa risks remain incompletely elucidated. Through two-sample Mendelian randomization (MR), this research seeks to assess the causal links between 4 genetically predicted SES indicators-average total household income before tax, the Townsend deprivation index at recruitment, unemployed status and college or university degree in the household-and PCa. Genetic variants were extracted from publicly available genome-wide association studies (GWAS) under stringent threshold as instrumental variables (IVs). We employed the inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger to estimate the causal effect, with sensitivity analyses such as Cochran's Q tests, MR-Egger, MR-PRESSO and leave-one-out performed to detect potential heterogeneity and pleiotropy. Our MR analysis revealed a causal association between unemployment and prostate cancer (OR: 3.07, 95%CI:1.12-8.42, P = 0.03). No causal associations were identified between other SES components and prostate cancer. The MR-PRESSO suggested 2 outliers in the association between college or university degree in household and prostate cancer, which rendered the association significant after outliers were removed. The heterogeneity and pleiotropy are unlikely to affect our causal estimate. Our results indicated that unemployment poses a potential risk factor for the incidence of PCa. The findings highlight the necessity for further exploration into the underlying etiology of PCa., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: This article is a Mendelian randomization study. The data for this study were obtained from publicly available databases and published literature data and does not require ethical approval and written informed consent., (© 2025. The Author(s).)

This study aims to explore the causal relationships between serum uric acid level and pulmonary arterial hypertension (PAH) using the Mendelian randomization (MR) approach, and to assess the therapeutic impacts of urate-lowering drugs on PAH. Utilizing published genome-wide association study (GWAS) data, we applied MR and colocalization analysis to assess the link between serum uric acid levesl and PAH across four GWAS datasets from two distinct European populations. The validity and reliability of these findings were confirmed through multiple statistical methods, along with an MR analysis of urate-lowering drug targets to investigate their potential effects on PAH treatment. MR analysis revealed a significant positive correlation between serum uric acid levels and PAH (odds ratio (OR) 1.106, 95% confidence intervals (CI) 1.021-1.200, P = 0.014), corroborated by a replication MR analysis (OR 1.859, 95% CI 1.130-3.057, P = 0.015). No significant heterogeneity or horizontal pleiotropy was found in the sensitivity analyses. However, urate-lowering drugs did not demonstrate a significant direct therapeutic effect on PAH. This study establishes a genetic basis for a causal link between serum uric acid levels and PAH. However, urate-lowering drugs do not appear to have a direct causal effect on improving PAH. These findings provide a novel reference point for developing future therapeutic strategies for PAH., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: The research involving humans has been approved by the GWAS database data (free access to the data is available upon approval by the administrator). These studies were carried out in accordance with local legislation and institutional requirements. Participants provided written informed consent for their participation in this study., (© 2025. The Author(s).)

Previous studies have indicated a significantly higher prevalence of breast cancer (BC) among female patients with meningioma compared to the general female population. Therefore, this study aimed to assess the causal relationship between BC and meningioma at the genetic level. Genetic instrumental variables (IVs) for BC were identified from the Breast Cancer Association Consortium (BCAC), the Discovery Biology and Risk of Inherited Variants in Breast Cancer Consortium (DRIVE), the Collaborative Oncological Gene-environment Study (iCOGS), and 11 other BC genome-wide association studies (GWAS). Meningioma GWAS data were obtained from the FinnGen consortium and were further divided into intracranial and spinal meningioma groups for analysis. The primary analysis employed the inverse-variance weighted (IVW) method, supported by sensitivity analysis to address pleiotropy and enhance robustness. Next, linkage disequilibrium score regression (LDSC) was used to assess the genetic correlation between BC and meningioma. Finally, we applied the Functional Mapping and Annotation (FUMA) platform to conduct an in-depth analysis of the GWAS data. After rigorous screening and Mendelian randomization (MR) tests, genetically predicted overall BC (OR: 1.17, P = 0.0045) and ER(estrogen receptors) + BC (OR: 1.21, P = 0.0006) showed a potential causal association with intracranial meningioma. No causal relationships were found between intracranial meningioma and three BC subtypes. No bidirectional causal relationships were found between spinal meningioma and any BC subtype. The LDSC results suggested a modest positive genetic correlation between overall BC (rg: 0.152, SE: 0.077, P = 0.048), ER + BC (rg: 0.181, SE: 0.086, P = 0.035), and intracranial meningioma. FUMA analysis identified PITPNB, TTC28, and CHEK2 as shared risk genes between overall BC, ER + BC, and intracranial meningioma. These findings suggest that BC, especially ER + BC, may be a risk factor for intracranial meningioma. ER-related signaling pathways and the regulation of DNA damage may play a critical role in the pathogenesis of both diseases., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All GWAS databases were publicly available and had been approved by the corresponding ethical review board in the original GWAS., (© 2025. The Author(s).)

This study aimed to investigate the potential association between white blood cell counts and the risk of lung cancer, including its subtypes, through Mendelian randomization (MR) analysis. We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics for the both exposure traits (eosinophil count, neutrophil count, lymphocyte count, monocyte count, basophil count, and total white blood cell count) and outcome traits (lung cancer and its subtypes). The GWAS dataset for lung cancer included 29,266 cases (11273 lung adenocarcinoma (LUAD), 7426 lung squamous cell carcinoma (LSCC), 2664 small cell lung cancer (SCLC)) and 56,450 controls. In MR analysis, we employed methods such as Inverse variance weighted (IVW), weighted median, MR-Egger regression, MR pleiotropy residual sum and outlier. MR analysis revealed an elevated total white blood cell (WBC) count significantly increased the risk of LUAD (IVW: OR = 1.484, 95% CI = 1.219-1.749, p = 0.003). The results confirmed a causal relationship between monocyte count and LUAD (IVW: OR = 1.687, 95% CI:1.542-1.830, p < 0.001). An increased total WBC count was associated with a higher risk of LUAD. Additionally, analysis of WBC subtypes counts indicated that monocyte count plays an crucial role in the elevated risk of LUAD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics declarations: There was no need to get informed consent or ethical approval for this study again because all of the data were taken from published sources, and the informed consent and approval were received., (© 2025. The Author(s).)

The links between Thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) has received widespread attention, but the causal relationships and mediating factors have not been systematically studied. We used two-sample Mendelian randomization (MR) analysis to elucidate the causal relationship between TDFDs and OP. Moreover, we performed mediation MR analyses to explore the role of thyroid-related hormones and OP risk factors in the association between TDFDs and OP. Two sample MR analyses showed that hyperthyroidism increased OP (OR = 1.080, 95% CI 1.026 to 1.137; P = 0.0032) risk. Hypothyroidism increases OP (OR = 1.183, 95% CI 1.125 to 1.244; P < 0.0001) risk. Furthermore, mediation analysis revealed that TSH mediated 5.314% of the relationship between hypothyroidism and OP. In contrast, FT4 mediated 9.670% of the relationship between hyperthyroidism and OP. In European populations, TDFDs may increase OP risk. TSH mediates in the causal association between hypothyroidism and OP, and similarly, FT4 mediates in the causal link between hyperthyroidism and OP. Our findings underscore the significance of improving integrative care for individuals with TDFDs to mitigate the risk of OP. It is essential to maintain stable levels of thyroid hormones and closely monitor bone health to effectively mitigate and prevent OP., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Fibromyalgia (FM) is a prevalent chronic pain condition with a complex and not fully understood etiology. Abnormal metabolism of trace elements is suspected to play a role in the pathogenesis of FM, though the exact relationships have yet to be clarified. This study employed Mendelian randomization (MR) to assess potential causal relationships between 15 major trace elements and the risk of FM, focusing on the specific roles of elements that show significant associations. Genetic instrumental variables (single nucleotide polymorphisms, SNPs), related to these trace elements and FM were extracted from genome-wide association studies (GWAS). Analyses were performed using various methods including inverse-variance weighting (IVW), MR Egger, weighted median, weighted mode, and simple mode. Furthermore, multivariable analysis controlled for selenium as a potential confounder to evaluate the independent associations of copper (Cu) and iron (Fe) with FM risk. Two-sample MR analysis indicated a positive association between Cu and increased risk of FM (IVW: OR = 1.095, 95% CI: 1.015 to 1.181, P = 0.018), and a negative association between Fe and FM risk (IVW: OR = 0.440, 95% CI: 0.233 to 0.834, P = 0.011). These associations remained significant in the multivariable analysis, highlighting the independent effects of Cu and Fe. No significant correlations were observed with other trace elements such as selenium and zinc. This study provides new evidence of the roles of Cu and Fe in the pathophysiology of FM and underscores the importance of considering trace elements in the prevention and treatment strategies for FM. Future research should further validate these findings and explore the specific biological mechanisms through which Cu and Fe influence FM risk., Competing Interests: Declarations. Competing interests: The authors declare that this study was conducted without any commercial or financial relationship, which could be interpreted as a potential conflict of interest. Ethical approval: was not required for this study involving human data, in accordance with local legislation and institutional requirements. Similarly, written informed consent to participate was not necessary from the participants or their legal guardians/next of kin, as per national legislation and institutional guidelines. These decisions were based on the fact that the study used de-identified, publicly available data sets where participants’ privacy and confidentiality are inherently protected. institutional requirements., (© 2025. The Author(s).)

Several observational studies have revealed that immune-mediated inflammatory diseases (IMIDs) are associated with an increased risk of peripheral artery disease (PAD). However, the causal association remains to be determined. To corroborate previous research, we conducted Mendelian randomization (MR) analysis with the aim of clarifying the associations of various IMIDs with PAD. two-sample MR analysis was conducted to investigate the potential causal association between eight common IMIDs (including rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), ankylosing spondylitis(AS), psoriasis(PSO), multiple sclerosis(MS), and hashimoto thyroiditis(HT)) and PAD. Genome-wide association study (GWAS) was used to identify genetic variants associated with IMIDs and PAD. We employed the inverse variance weighted (IVW) method as the primary method to verify the causal relationship between exposures (IMIDs) and outcomes (PAD). In addition, heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis were performed to evaluate the robustness of the MR results. The IVW model yielded evidence of a positive association between RA and PAD (OR = 1.059, 95% CI: 1.026-1.094, p<0.001), which was consistent with the results obtained from MR-Egger regression and weighted median analyses, indicating that the results of MR analysis were reliable. However, no statistically significant associations were observed between other IMIDs, including UC, CD, SLE, AS, PSO, MS, and HT, and PAD. Our analysis supported the causal association of RA with increased risks of PAD. Strengthening screening and prevention of PAD is of great significance in reducing the risk of PAD in populations with RA., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Observational studies have reported an association between lipoprotein(a) (Lp(a)) and immune-mediated inflammatory diseases (IMIDs). This study used Mendelian Randomization (MR) and multivariable MR (MVMR) to explore the causal relationship between lipoprotein(a) [Lp(a)] and immune-mediated inflammatory diseases (IMIDs). We performed a bidirectional two-sample mendelian randomization analyses based on genome-wide association study (GWAS) summary statistics of Lp(a) and nine IMIDs, specifically celiac disease (CeD), Crohn's disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis (Pso), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and summary-level data for lipid traits. Furthermore, we performed MVMR to examine the independence of relationship between Lp(a) and IMIDs after controlling other lipid traits, namely high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). We didn't observe a causal association between Lp(a) and the risk of IMIDs in univariable and multivariable MR analysis, challenging previous observational studies. However, genetically predicted lipid traits HDL-C was associated with increased risk of Type 1 diabetes (T1D). The identification of potential mechanisms underlying the observed associations in observational studies necessitates further investigation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Multiple myeloma (MM) is an incurable blood cancer with unclear aetiology. Proteomics is a valuable tool in exploring mechanisms of disease. We investigated the causal relationship between circulating proteins and MM risk, using two of the largest cohorts with proteomics data to-date. We performed bidirectional two-sample Mendelian randomization (MR; forward MR = causal effect estimation of proteins and MM risk; reverse MR = causal effect estimation of MM risk and proteins). Summary statistics for plasma proteins were obtained from genome-wide association studies performed using SomaLogic (N = 35,559; deCODE) and Olink (N = 34,557; UK Biobank; UKB) proteomic platforms and for MM risk from a meta-analysis of UKB and FinnGen (case = 1649; control = 727,247) or FinnGen only (case = 1085; control = 271,463). Cis-SNPs associated with protein levels were used to instrument circulating proteins. We evaluated proteins for the consistency of directions of effect across MR analyses (with 95% confidence intervals not overlapping the null) and corroborating evidence from genetic colocalization. In the forward MR, 994 (SomaLogic) and 1570 (Olink) proteins were instrumentable. 440 proteins were analysed in both deCODE and UKB; 302 (69%) of these showed consistent directions of effect in the forward MR. Seven proteins had 95% confidence intervals (CIs) that did not overlap the null in both forward MR analyses and did not have evidence for an effect in the reverse direction: higher levels of dermatopontin (DPT), beta-crystallin B1 (CRYBB1), interleukin-18-binding protein (IL18BP) and vascular endothelial growth factor receptor 2 (KDR) and lower levels of odorant-binding protein 2b (OBP2B), glutamate-cysteine ligase regulatory subunit (GCLM) and gamma-crystallin D (CRYGD) were implicated in increasing MM risk. Evidence from genetic colocalization did not meet our threshold for a shared causal signal between any of these proteins and MM risk (h4 < 0.8). Our results highlight seven circulating proteins which may be involved in MM risk. Although evidence from genetic colocalization suggests these associations may not be robust to the effects of horizontal pleiotropy, these proteins may be useful markers of MM risk. Future work should explore the utility of these proteins in disease prediction or prevention using proteomic data from patients with MM or precursor conditions., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. , (© 2025. The Author(s).)

This study aimed to elucidate the potential causal relationship between 4,907 plasma proteins and the risk of gastric cancer using a two-sample Mendelian randomization approach. We utilized genome-wide association study (GWAS) data to perform two-sample Mendelian randomization analyses, treating the 4,907 plasma proteins as exposure factors and gastric cancer as the outcome. Instrumental variables for plasma proteins were selected based on strongly correlated SNPs identified through data processing and screening of the GWAS data provided by the deCode database. We employed a set of statistical methods centered on inverse variance weighting (IVW) for Mendelian randomization analysis to estimate the odds ratios (ORs) for the effects of these plasma proteins on gastric cancer susceptibility. According to the IVW method, 14 plasma proteins were associated with gastric cancer (p < 0.005). Specifically, CHST15 (OR = 0.7553, 95% CI = 0.6346 - 0.8988), L1CAM (OR = 0.7230, 95% CI = 0.5876 - 0.8896), FTMT (OR = 0.8246, 95% CI = 0.7241 - 0.9391), and PMM2 (OR = 0.5767, 95% CI = 0.3943 - 0.8433) were negatively correlated with GASTRIC CANCER, whereas ABO (OR = 1.1868, 95% CI = 1.0638 - 1.3240), FAM3D (OR = 1.2109, 95% CI = 1.0850 - 1.3515), FAM3B (OR = 1.2988, 95% CI = 1.0953 - 1.5402), ADH7 (OR = 1.3568, 95% CI = 1.1044 - 1.6670), MAP1LC3A (OR = 1.3704, 95% CI = 1.1194 - 1.6778), PGLYRP1 (OR = 1.4071, 95% CI = 1.1235 - 1.7623), PDE5A (OR = 1.7446, 95% CI = 1.2693 - 2.3978), GLUL (OR = 3.1203, 95% CI = 1.5017 - 6.4839), NFE2L1 (OR = 3.1759, 95% CI = 1.6163 - 6.2402), and MAFG (OR = 3.1945, 95% CI = 1.5329 - 6.6575) were positively correlated. Convergent results from Weighted Median and MR-Egger analyses confirmed these associations. Reverse Mendelian randomization analysis indicated that gastric cancer does not significantly alter the levels of these 14 plasma proteins (p > 0.05). Sensitivity analyses, including assessments of heterogeneity and horizontal pleiotropy, confirmed the robustness and reliability of our findings without significant bias. Pathway enrichment analysis of gene expression associated with these 14 plasma proteins, using GO and KEGG pathways, revealed that CHST15, L1CAM, FTMT, and PMM2 may serve as protective factors against gastric cancer, while ABO, FAM3D, FAM3B, ADH7, MAP1LC3A, PGLYRP1, PDE5A, GLUL, NFE2L1, and MAFG may contribute to gastric cancer pathogenesis. These results highlight the complex biological interactions between plasma proteins and tumorigenesis, providing valuable insights for preventive and therapeutic strategies in gastric malignancy management., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

With the rapid advancement of proteomics, numerous scholars have investigated the intricate relationships between plasma proteins and various diseases. Therefore, this study aims to elucidate the relationship between BDH1 and type 2 diabetes using Mendelian randomization (MR) and to identify novel targets for the prevention and treatment of type 2 diabetes through proteomics. This study primarily employed the Mendelian Randomization (MR) method, leveraging genetic data from numerous large-scale, publicly accessible genome-wide association studies (GWAS). Within this framework, we adopted a two-step, two-sample MR approach to evaluate the relationships between BDH1, plasma proteins, and type 2 diabetes. Finally, we conducted bidirectional MR analyses along with various sensitivity analyses to ensure the robustness and reliability of the study findings. The inverse variance weighted (IVW) analysis demonstrated that for each 1 standard deviation (SD) increase in BDH1, the risk of type 2 diabetes decreased by 3% (OR: 0.97; 95% CI: 0.95, 0.99). Concurrently, the proteomics-based MR analysis identified 37 plasma proteins associated with type 2 diabetes and 27 plasma proteins associated with BDH1. Notably, NBN, ARG1, and CCL11 were found to mediate the protective effect of BDH1 on type 2 diabetes. Our research findings uncovered the potential protective effect of BDH1 on type 2 diabetes and identified several plasma proteins associated with the disease. These results open new avenues for enhanced exploration of the prevention and treatment of type 2 diabetes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study is based on publicly available summarized data. Ethical approval and informed consent had been obtained in all original studies., (© 2025. The Author(s).)

Benign prostatic hyperplasia (BPH) is a prevalent urinary system disorder. Despite evidence of a significant genetic component from previous studies, the specific pathogenic genes and biological mechanisms are still largely unknown. The study utilized the FinnGen R10 dataset, encompassing 177,901 individuals (36,601 cases and 141,300 controls), and the GTEx v8 EQTLs files to conduct single-tissue and cross-tissue transcriptome-wide association studies (TWAS). FUSION method was utilized to validate the findings in specific tissues. Gene Analysis and Multi-marker Analysis of Genomic Annotation (MAGMA) were used to identify potential susceptibility genes. The intersection genes of the above results were analyzed by Mendelian randomization (MR), summary data-based MR (SMR) and colocalization studies. Fine-mapping of causal gene sets (FOCUS) software was employed to accurately locate risk genes. Gene Expression Omnibus (GEO) analysis explores the differential expression of genes. Finally, The GeneMANIA tool was utilized to further understand the functional roles of these susceptibility genes. The cross-tissue TWAS analysis revealed 28 genes associated with BPH susceptibility. Single-tissue TWAS and MAGMA further refined eight genes, and subsequent MR, SMR, FOCUS and colocalization analysis pinpointed INO80B as the key gene. The differential expression of this result was verified by GEO. INO80B may help prevent excessive prostatic cell proliferation by regulating cell cycle-related gene expression. Our research identified the INO80B gene, whose predicted expression is associated with BPH risk and hence provided a new insight into the genetic basis of this disease. However, further functional studies are necessary to elucidate the potential biological activity of these significant signals., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Previous studies have found that dyslipidemia is a risk factor for pancreatic cancer (PC), and that lipid-lowering drugs may reduce the risk of PC. However, it is not clear whether dyslipidemia causes PC. The Mendelian randomization (MR) study aimed to investigate the causal role of lipid traits in pancreatic cancer and to assess the potential impact of lipid-lowering drug targets on pancreatic cancer. Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for PC were obtained from an independent GWAS datasets. Colocalization analyses were performed to validate the robustness of the results. No significant effect of lipid-lowering drug targets on PC risk was found. Genetic mimicry of lipoprotein lipase (LPL) was potentially associated with PC risks. Significant MR associations were observed in the discovery dataset (OR 1.64 [95% CI 1.24-2.16], p = 4.48*10 -4 ) with PC in one dataset. However, the finding was not verified in the replication dataset. Our findings do not support dyslipidemia as a causal factor for PC. Among lipid-lowering drug targets, LPL is the potential drug target in PC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Retinal vein occlusion (RVO) is the leading cause of vision loss due to an obstruction in the retinal venous system. While RVO is often linked to thrombotic tendencies and coagulation abnormalities, the exact role of coagulation traits in its development is not fully understood. This study aims to investigate the potential causal relationship between coagulation traits and the risk of RVO by analyzing publicly available genome-wide association study (GWAS) summary statistics. A two-sample Mendelian randomization (MR) analysis framework was employed to investigate the causal relationship between coagulation traits and the risk of RVO. Stringent quality control measures were applied to select appropriate instrumental variables strongly linked to exposure, such as coagulation factor III (FIII), coagulation factor V (FV), coagulation factor VIII (FVIII), coagulation factor XI (FXI), coagulation factor VII (FVII) and coagulation factor X (FX), as well as plasmin, platelet count, platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). The study utilized the FinnGen project RVO GWAS summary statistics cohort, consisting of 372 RVO cases and 182,573 controls. The analysis focused on 11 coagulation traits. The research suggests that genetically predicted plasma levels of FIII, FVII, MPV, and PCT may be potentially causative for reducing the risk of RVO, and that levels of FVIII may be potentially causative for increasing the risk of RVO. Our MR analysis, utilizing GWAS data from a comprehensive population-based study, revealed a causal association between plasma levels of FIII, FVII, FVIII, MPV, and PCT with the risk of RVO., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This MR study, which exclusively utilized publicly available summary statistics, was exempt from ethical approval. Patient and public involvement: It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research., (© 2025. The Author(s).)

This study focused on the relationships among gut microbiota, plasma protein ratios, and tuberculosis. Given the unclear causal relationship between gut microbiota and tuberculosis and the scarcity of research on relevant plasma protein ratios in tuberculosis, Mendelian randomization analysis (MR) was employed for in-depth exploration. By analyzing the GWAS data of individuals with European ancestry (the FinnGen dataset included 409,568 controls and 2613 cases), using the two-sample MR method, we focused on evaluating the impact of immunocyte-mediated gut microbiota on tuberculosis and the associations between 2821 plasma protein-to-protein ratios and tuberculosis. Particularly, the mediation effect was emphasized in the exploration. The results showed that 19 gut microbiotas were associated with tuberculosis. An7 indirectly affected tuberculosis through immunocyte (CD4 on CM CD4+), with a masking effect ratio of 0.008, demonstrating immune cells' mediating role in the association between gut microbiota and tuberculosis. Meanwhile, the MR analysis revealed that 127 plasma protein-to-protein ratios were associated with tuberculosis. In conclusion, this study not only confirmed the impact of immunocyte-mediated gut microbiota on tuberculosis and clarified the mediating mechanism therein but also identified plasma protein-to-protein ratios related to tuberculosis, providing novel and valuable ideas for diagnosing and treating tuberculosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Previous studies have shown that serum albumin levels are associated with a greater risk of metabolic syndrome (MetS). However, it is unclear whether this association is causal or only influenced by confounding factors, so further investigation is needed to determine the causal relationships. Researchers selected participants with serum albumin, metabolic syndrome, and related covariates from the National Health and Nutrition Examination Survey (NHANES) database for a total of 14,036 individuals, including 5483 individuals with MetS and 8553 individuals without MetS. The association of serum albumin levels with metabolic syndrome and its components was estimated using weighted multivariable logistic regression, with its nonlinearity being examined by restricted cubic spline (RCS) regression. Bidirectional two-sample Mendelian randomization (MR) analysis was performed using Genome-Wide Association Study (GWAS) data on serum albumin and MetS to assess the causal relationship between serum albumin levels and MetS and its components. The primary MR analyses were performed via an inverse variance weighting (IVW) approach. In addition, several sensitivity analyses were performed to assess the robustness of the results. The STROBE-MR checklist for the reporting of MR studies was used in this study. After confounder adjustment, when the serum albumin levels were analyzed as a continuous variable, the multivariable logistic analysis revealed a significant association between it and metabolic syndrome (OR: 1.032, 95% CI: 1.012-1.052). When the serum albumin levels were used as categorical variables, the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for metabolic syndrome across higher serum albumin levels quartiles were 0.981 (0.842-1.143), 1.290 (1.115-1.492), and 1.244 (1.064-1.454) compared to the lowest quartile, respectively. In the forward MR study, the IVW method revealed that genetic predicted increased levels of serum albumin were positively correlated with metabolic syndrome (OR: 1.149, 95% CI: 1.016-1.299) and its components, including hypertension (OR: 1.130, 95% CI: 1.013-1.260) and triglycerides (OR: 1.343, 95% CI: 1.209-1.492). In the reverse MR study, the IVW method showed no significant causal relationship between MetS, hypertension, fasting blood glucose and HDL-C with serum albumin levels. The results from the NHANES and MR analysis have revealed a causal relationship between serum albumin levels and both metabolic syndrome and hypertension, indicating that elevated levels of serum albumin are a risk factor for these conditions. Our results provide new biomarkers for preventive and therapeutic strategies for metabolic syndrome., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics statement: The survey protocols of the NHANES were approved by the Research Ethics Review Board of the National Center for Health Statistics ( https://www.cdc.gov/nchs/nhanes/irba98.htm ), and all survey participants provided informed consent., (© 2025. The Author(s).)

Dietary factors have recently been recognized as potentially influential in the pathogenesis of endometriosis (EM), yet studies on the causal relationship between dietary preferences and EM are limited. The present study aimed to explore the causal relationships between 187 dietary preferences and EM using Mendelian randomization (MR) methods. This study utilised genome-wide association study data from over 500,000 European participants for dietary preferences and 64,658 EM patients from Finland. Dietary preferences with potential causal relationships to EM were identified using two-sample MR methods. P-values from the inverse variance weighted (IVW) analysis were corrected using the false discovery rate (FDR) method to ensure accuracy. Additionally, heterogeneity analysis, pleiotropy assessment, leave-one-out analysis, and reverse MR analysis were conducted to further validate and solidify the findings of the study. After FDR correction, IVW analysis revealed that asparagus preference was significantly protective against EM, including in American Society for Reproductive Medicine (ASRM) stages 1-2 and 3-4. Conversely, preferences for different types of coffee and orange juice were associated with an increased likelihood of EM across these stages. Subgroup analysis indicated that asparagus preference had a protective effect against deep EM, ovarian EM, pelvic peritoneal EM, and rectovaginal septum and vaginal EM. In contrast, coffee preference increased the risk of pelvic peritoneal EM, fallopian tube EM, and unspecified EM, whereas orange juice preference increased the risk of deep EM, rectovaginal septum and vaginal EM, pelvic peritoneal EM, and unspecified EM. Reverse MR analysis did not identify causal relationships between EM and the specific dietary preferences that were analysed in this study. These findings suggest that asparagus preference significantly reduces the risk of developing EM, whereas preferences for orange juice and different types of coffee may increase the risk, offering new insights into EM management through dietary modifications., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The analyses were based on publicly available data that have been approved by relevant review boards., (© 2025. The Author(s).)

Gliomas are a prevalent form of primary malignant brain tumor, yet the intricate molecular mechanisms underlying its pathogenesis remain unclear. This study aimed to identify new genetic targets linked to glioma by analyzing microarray datasets to uncover genetic factors involved in its onset and progression. We obtained two independent glioma datasets from the Gene Expression Omnibus database, processed and normalized them using R software, and evaluated the relationship between differentially expressed genes and glioma by differential expression, expression quantitative trait loci, and Mendelian randomization (MR) analyses. Gene set enrichment analysis and immunocytometric analysis further explored the biological functions and pathways of identified genes, which were validated using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. We identified eight co-expressed genes-C1QB, GPX3, LRRC8B, TRIOBP, SNAPC5, SPI1, TSPYL5, and FBXL16-that are crucial in various biological processes. CIBERSORT analysis revealed significant immune cell-type distributions within gliomas, underscoring the significance of immune cell infiltration. Validation in additional datasets confirmed the MR analysis results and upstream regulatory factors were identified using NetworkAnalyst. Our findings offer fresh perspectives on the molecular underpinnings of glioma and highlight potential targets for therapeutic interventions., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical statement: All analyses of raw data in this study have received ethical approval from the respective institutional review boards., (© 2025. The Author(s).)

This study aimed to assess the causal relationship between lipidome and female reproductive diseases (FRDs) using an advanced series of Mendelian randomization (MR) methods. This study utilized genome-wide association study (GWAS) summary statistics encompassing 179 lipidomes and six prevalent FRDs, namely polycystic ovary syndrome (PCOS), endometriosis, uterine fibroid, female infertility, uterine endometrial cancer, and ovarian cancer. The two-sample MR (TSMR) approach was employed to investigate the causal relationships, with further validation using false discovery rate (FDR) and multivariable MR (MVMR) methods. Subsequently, a range of comprehensive evaluations were performed, including sensitivity analysis, mediation MR analysis, reverse MR analysis, and steiger test. Examining 179 lipidome traits as exposures and 6 FRDs as outcomes, this study identified significant causal effects of 56 lipids on FRDs. Following multiple testing correction and MVMR validation, sphingomyelin (d38:2) was found to have a protective effect against PCOS (β = -0.104, 95% CI: -0.199 ~ -0.010, P = 0.031). Phosphatidylcholine (18:0&#95;22:6) was associated with a decreased risk of developing uterine fibroid (β = -0.111, 95% CI: -0.201~ -0.021, P = 0.016), and sterol ester (27:1/20:3) showed significance in uterine endometrial cancer (β = -0.248, 95% CI: -0.443 ~ -0.053, P = 0.013). Conversely, phosphatidylethanolamine (18:2&#95;0:0) was associated with increased risk of endometriosis (β = 0.183, 95% CI: 0.015 ~ 0.350, P = 0.033), while sterol ester (27:1/18:1) posed a risk influence on uterine fibroid (β = 1.007, 95% CI: 0.925 ~ 1.089, P < 0.001), and phosphatidylcholine (16:0&#95;22:6) on uterine endometrial cancer (β = 0.229, 95% CI: 0.039 ~ 0.420, P = 0.018). Furthermore, it was determined that the causal associations between these lipidome profiles and FRDs were independent of BMI, obesity, diabetes, smoking, alcohol use, physical activity, inflammation, depression, waist-hip ratio, vitamin D, dehydroepiandrosterone sulphate, sex hormone binding globulin, and testosterone levels. Most outcomes passed consistent tests without evidence of heterogeneity, pleiotropy, or reverse causality. The results indicated a close association between specific lipidomes, particularly sphingomyelin, lysophosphatidylethanolamine, cholesterol ester, and phosphatidylcholines, with FRDs. These lipid species may potentially serve as biomarkers and future drug targets for the treatment of FRDs., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: The data used in this study were sourced from publicly available datasets, originally collected from studies that had received prior approval from an ethics committee for human experimentation. Therefore, our study did not require additional ethical approval., (© 2025. The Author(s).)

Parkinson's disease (PD) is a complex neurodegenerative disorder influenced by both genetic and environmental factors, including dietary habits. Despite considerable research, the relationship between food intake and PD risk remains poorly understood. Here, we conducted a comprehensive Mendelian randomization analysis to investigate the association between a wide spectrum of food intake and PD risk. Utilizing data from large-scale genome-wide association studies (GWAS) and dietary databases, we constructed genetic instruments for various dietary factors, including fruit, vegetable, meat, fish, dairy, and grain intake, among others, totaling 170 different food items. Using multivariable inverse variance weighted methods, we found a causal relationship between Mozzarella intake and Parkinson's disease (odds ratio [OR] = 9.83, 95% confidence interval [CI] = 2.52-38.34, P-value < 0.05). Additionally, a causal relationship was observed between Pancake intake and Parkinson's disease (odds ratio [OR] = 0.20, 95% confidence interval [CI] = 0.07-0.59, P-value < 0.05). Furthermore, our reverse Mendelian randomization analysis and multivariable Mendelian randomization analysis provided further support for these findings. To our knowledge, we are the first to investigate the causal relationship between the broad intake of 170 different food items and Parkinson's disease. Our study reveals the causal relationships between Pancake intake, and Mozzarella intake with Parkinson's disease., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Interstitial lung disease (ILD) has shown limited treatment advancements, with minimal exploration of circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify potential drug targets and circulating protein biomarkers for ILD and its subtypes. We utilized the most recent large-scale plasma protein quantitative trait loci (pQTL) data detected from the antibody-based method and ILD and its subtypes' GWAS data from the updated FinnGen database for Mendelian randomization analysis. To enhance the reliability of causal associations, we conducted external validation and sensitivity analyses, including Bayesian colocalization and bidirectional Mendelian randomization analysis. Our study identified eight plasma proteins genetically associated with ILD or its subtypes. Among these, three proteins-CDH15 (Cadherin-15), LTBR (Lymphotoxin-beta receptor), and ADAM15 (A disintegrin and metalloproteinase 15)-emerged as priority biomarkers and potential therapeutic targets, demonstrating more reliable associations by passing a series of sensitivity analyses compared to the others. Based on these findings, we propose for the first time that CDH15, ADAM15, and LTBR hold promise as novel potential circulating protein biomarkers and therapeutic targets for the diagnosis and treatment of ILD, IPF, and sarcoidosis, respectively, especially ADAM15, and these findings have the potential to provide new perspectives for advancing the research on the heterogeneity of ILD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Traditional epidemiological studies are susceptible to confounding factors. To clarify the impact of metabolic syndrome and its diagnostic components on hepatocellular carcinoma, we conducted a preliminary mendelian randomization analysis with metabolic syndrome and its diagnostic components as exposures and hepatocellular carcinoma as the outcome. Another set of genetic data related to hepatocellular carcinoma was used as a validation cohort, repeating the mendelian randomization analysis and combining the two groups for a meta-analysis. Preliminary analysis showed that metabolic syndrome (P-value = 0.002) and waist circumference (P-value = 0.026) are significantly positively correlated with an increased risk of hepatocellular carcinoma. After multiple testing corrections, metabolic syndrome (P FDR -value = 0.013) remained significant, although the association between waist circumference (P FDR -value = 0.079) and hepatocellular carcinoma was considered suggestive, the meta-analysis further confirmed the impact of metabolic syndrome (P-value = 0.0002) and waist circumference (P-value = 0.0038) in increasing the risk of hepatocellular carcinoma. After adjusting for the genetic predictive effects of all exposures, waist circumference was found to be a key factor significantly influencing the relationship between metabolic syndrome and hepatocellular carcinoma. In summary, our study indicates that metabolic syndrome increases the risk of hepatocellular carcinoma, particularly among individuals with a larger waist circumference., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction, is a major cause of secondary hypertension with significant cardiovascular complications. Current treatments mainly focus on symptom management rather than addressing underlying mechanisms. This study aims to discover novel therapeutic targets for PA using integrated bioinformatics and experimental validation approaches. We employed a systematic approach combining: gene identification through transcriptome-wide association studies (TWAS); causal inference using summary data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (MR) analyses; additional analyses included phenome-wide association analysis, enrichment analysis, protein-protein interaction (PPI) networks, drug repurposing, molecular docking and clinical validation through aldosterone-producing adenomas (APAs) tissue. Through systematic screening and prioritization, we identified 163 PA-associated genes, of which seven emerged as potential drug targets: CEP104, HIP1, TONSL, ZNF100, SHMT1, and two long non-coding RNAs (AC006369.2 and MRPL23-AS1). SHMT1 was identified as the most promising target, showing significantly elevated expression in APAs compared to adjacent non-tumorous tissues. Drug repurposing analysis identified four potential SHMT1-targeting compounds (Mimosine, Pemetrexed, Leucovorin, and Irinotecan), supported by molecular docking studies. The integration of multiple bioinformatics methods and experimental validation successfully identified novel drug targets for hyperaldosteronism. SHMT1, in particular, represents a promising candidate for future therapeutic development. These findings provide new opportunities for developing causative treatments for PA, though further clinical validation is warranted., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All procedures involving human tissue samples were approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital of Zhejiang University School of Medicine, and written informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki., (© 2025. The Author(s).)

Non-small cell lung adenocarcinoma (LUAD) is a markedly heterogeneous disease, with its underlying molecular mechanisms and prognosis prediction presenting ongoing challenges. In this study, we integrated data from multiple public datasets, including TCGA, GSE31210, and GSE13213, encompassing a total of 867 tumor samples. By employing Mendelian randomization (MR) analysis, machine learning techniques, and comprehensive bioinformatics approaches, we conducted an in-depth investigation into the molecular characteristics, prognostic markers, and potential therapeutic targets of LUAD. Our analysis identified 321 genes significantly associated with LUAD, with CENP-A, MCM7, and DLGAP5 emerging as highly connected nodes in network analyses. By performing correlation analysis and Cox regression analysis, we identified 26 prognostic genes and classified LUAD samples into two molecular subtypes with significantly distinct survival outcomes. The Random Survival Forest (RSF) model exhibited robust prognostic predictive capabilities across multiple independent cohorts (AUC > 0.75). Beyond merely predicting patient outcomes, this model also captures key features of the tumor immune microenvironment and potential therapeutic responses. Functional enrichment analysis revealed the complex interplay of cell cycle regulation, DNA repair, immune response, and metabolic reprogramming in the progression of LUAD. Furthermore, we observed a strong correlation between risk scores and the expression of specific cytokines, such as CCL17, CCR2, and CCL20, suggesting novel avenues for developing cytokine network-based therapeutic strategies. This study offers fresh insights into the molecular subtyping, prognostic prediction, and personalized therapeutic decision-making in LUAD, laying a critical foundation for future clinical applications and targeted therapy research., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Consent for publication: All authors approved the final manuscript for publication., (© 2025. The Author(s).)

Inflammatory bowel disease (IBD) is a multisystem condition that could affect the cutaneous systems, namely cutaneous extraintestinal manifestations (EIMs). It has been suggested that IBD is associated with erythema nodosum (EN), malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, the potential causal relationship between IBD and the mentioned above cutaneous EIMs is still unclear. This study aims to determine the effect of IBD on EN, MM and NMSC within a Mendelian randomization (MR) design. Summary-level data for IBD, EN, MM, NMSC were obtained from large-scale genome-wide association studies. We utilized five different methods, including the inverse variance weighted model (IVW), MR Egger, Weighted median, Simple mode, Weighted mode in the MR analysis, then the Cochran's Q test, the MR-Egger pleiotropy test, the MR-PRESSO global pleiotropy test and leave-one-out sensitivity test were used to evaluate the heterogeneity and pleiotropy of identified IVs. To further ensure the validity of our findings, we evaluated the strength of the instrumental variables using the F-statistic and estimated the statistical power of our study. Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. MR analysis suggested that genetically determined IBD had a detrimental causal effect on NMSC (IVW: odds ratio [OR] = 1.002037, 95% confidence interval [CI] = 1.0001150-1.003962, P = 0.03776677), but not on EN (IVW: [OR] = 1.0937191, 95% [CI] = 0.9685831-1.235022, P = 0.1484349) and MM (IVW: [OR] = 0.9998064, 95% [CI] = 0.9994885-1.000124, P = 0.2326482). Besides, a positive causal effect of IBD on NMSC was verified in an independent validation dataset (IVW: [OR] = 1.002651, 95% [CI] = 1.0006524-1.004654, P = 0.009307506). The present study corroborated the causal relationship between IBD and NMSC. In contrast, our results showed no evidence of a causal association of IBD on EN and MM. These findings provide new insights into increasing attention to patients with IBD to prevent concurrent NMSC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Acute pancreatitis (AP) is a severe gastrointestinal condition with an increasing incidence of hyperlipidemic etiology. The investigation employed a two-sample, bidirectional Mendelian randomization method to investigate potential causal relationship between lipidome profiles, inflammatory mediators, and AP. Exploration of genetic variants across the genome in a study population of 10,630 AP cases and 844,679 non-AP individuals revealed multiple lipidome entities significantly associated with AP risk. The study identified 23 lipid species with unidirectional causal effects on AP after accounting for heterogeneity, pleiotropy, and potential reverse causation. Additionally, five inflammatory factors (CD5, IL-13, MMP-1, STAMBP, TNFRSF9) showed significant potential causal relationship with AP. Further analysis elucidated the intricate interplay between specific lipid species and inflammatory mediators in influencing AP incidence. Notably, Sterol ester (27:1/20:4) and several phosphatidylcholine species, including PC (17:0&#95;20:4), PC (18:0&#95;20:4), PC (18:0&#95;20:5), and PC (O-18:2&#95;20:4), were negatively associated with AP risk. This protective effect was partially mediated through decreased levels of inflammatory markers, particularly STAMBP and MMP-1. The study found that these phosphatidylcholines and sterol esters significantly reduced the levels of these pro-inflammatory factors, thereby potentially mitigating AP risk. Conversely, Phosphatidylinositol (16:0&#95;18:1) demonstrated a positive association with AP risk. This detrimental effect was partially mediated by increased levels of MMP-1 and STAMBP, suggesting a pro-inflammatory mechanism. The study provides evidence that this specific phosphatidylinositol species may exacerbate AP risk by promoting inflammatory pathways. These findings elucidate the complex interplay between lipid metabolites, inflammation, and AP pathogenesis, potentially informing novel therapeutic strategies. The study highlights the utility of Mendelian randomization in uncovering potential causal relationship in AP. It underscores the requirement for further study into the molecular mechanisms underlying lipid-mediated inflammation in AP, particularly the roles of phosphatidylcholines and sterol esters in modulating inflammatory responses. Further studies are warranted to confirm our observations in laboratory models and assess their translational value in developing AP preventive and therapeutic strategies., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Mendelian randomization (MR) was employed to investigate the causal relationships between immune cell phenotypes, hyperthyroidism (HD), and potential metabolic mediators. In this study, we acquired 731 immune cell phenotypes from genome-wide association studies (GWAS) (n = 18,622), HD data from the research by Handan Melike Dönertaş et al. (3,731 cases, 480,867 controls), and aggregated statistics of 1,400 blood metabolites from UK Biobank (n = 115,078). Bidirectional MR analysis was performed to explore the causal relationships between the immune cell phenotypes and HD, and two-sample and multi-variable MR were conducted to identify the potential plasma metabolites mediating in HD. In addition, sensitivity analyses were used to evaluate robustness, heterogeneity, and horizontal pleiotropy of results. Single-cell transcriptome-based exploration of potential key molecule and mechanism by which plasma metabolites regulated the immune cell differentiation in HD pathogenesis. Co-localization analysis was using single-cell eQTL (sc-eQTL) data with key molecule to probe genetically shared effects. Two-sample MRshowed that CD25 on naive-mature B cell, CD8 + NKT cell, and thymol sulfate level were found to have causal relationships with HD (P < 0.008). The causal relationship between thymol sulfate and HD were further validated in an independent cohort using the inverse-variance weighted (IVW). In addition, CD25 on naive-mature B cells and CD8 + NKT cells were both negatively correlated with thymol sulfate (P < 0.05). The results remained significant after MR-Egger and MR-PRESSO correction for horizontal pleiotropy and heterogeneity (P > 0.05). Multi-variable MR results showed that CD25 on naive-mature B cell and CD8 + NKT cell mediated 8.67% and 10.4% of the associations between thymol sulfate and HD, respectively. Moreover, thymol sulfate mediated the evolution of CD8 + NKT cells in the immune microenvironment, identifying PTPRC, PTK2B, KDM5A and TIGIT as the key participating molecules. Co-localization analysis showed that the key molecules had significant genetic sharing effects with CD8 + NKT cells (PPH4 > 0.75, R 2  > 0.8, P < 0.05), with PTK2B having the broadest sharing interval. Current MR study provides evidence supporting causal relationships between several specific immune cell phenotypes and HD, as well as potential mediating metabolites. Thymol sulfate may increases the risk of HD pathogenesis by mediating the evolution of PTK2B genetic variants inducing CD8 + NKT cells in the progression of the immune microenvironment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: Ethical approval was considered unnecessary, as the original studies had undergone ethical review and approval, and obtained written informed consent from all participants involved in the original genome-wide association studies. These studies were conducted in accordance with local legislation and institutional requirements. Participants provided written informed consent for participation in this study., (© 2025. The Author(s).)

Major depressive disorder (MDD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently occur together; yet their causal relationship remains unclear. To investigate the potential genetic causal link between these conditions, we conducted a two-sample Mendelian randomization (MR) analysis. Summary data from Genome-Wide Association Studies (GWAS) for MDD were sourced from the UK Biobank and the Psychiatric Genomics Consortium, while GWAS data for ME/CFS were retrieved from the UK Biobank. Inverse-variance weighting (IVW), the MR-Egger method, and weighted median, simple and weighted modes were used to perform the MR analysis. In addition, Cochrane's Q-test was used to detect heterogeneity among the MR results. Horizontal pleiotropy was detected using the MR-Egger intercept and the MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Leave-one-out analysis was performed to investigate the sensitivity of the association between MDD and ME/CFS. The results of the MR analysis revealed no causal relationship between MDD and ME/CFS. The pleiotropy test revealed that causality bias was improbable, and no evidence of heterogeneity was found among the genetic variants. Finally, the leave-one-out test confirmed the stability and robustness of our findings., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Benign paroxysmal vertigo (BPV) is a common cause of dizziness, and some patients are comorbid with psychiatric disorders such as depression, requiring intervention with antidepressants. However, the causal association between BPV, depression and antidepressants has not been clearly established. We used two-sample bidirectional Mendelian randomization (MR) to analyze the causal association between BPV, depression, and antidepressants. From a Finnish database, 43,280 patients with depression and 329,192 controls, and 106,785 patients with antidepressants and 88,536 controls were selected. Independent single nucleotide polymorphisms (SNPs) for depression and antidepressants were used as instrumental variables (IVs) with genomic significance (p < 5 × 10 -8 ). Similarly, genome-wide association study (GWAS) data for BPV were selected from a Finnish database consisting of 8280 cases and 359,094 controls. Afterwards, a two-sample MR study was performed using R's Two Sample MR and MR-PRESSO software packages. The multiplicity and heterogeneity of the data, as well as the effect of individual SNPs on the results were investigated. The main statistical analyses were weighted median, weighted mode, MR-Egger and weighted inverse variance weighting (IVW) for random effects. Finally, we identified associations between BPV, antidepressants and depression. Four outliers (rs3773087, rs4619804, rs62099231, rs7192848) were found to be associated with depression. After removing the outliers, the statistics showed no heterogeneity (p > 0.05) and horizontal pleiotropy (p > 0.05). Antidepressants were also found to have a random effect IVW (β = 0.440; p = 9.692 × 10 -6 ; OR = 1.553; 95% CI 1.278-1.887). The inverse MR random effects IVW results showed a causal association between BPV and antidepressants (β = 0.051; p = 0.045; OR = 1.052; 95% CI 1.001-1.1066). In conclusion, there was a significant causal association between antidepressants and BPV at the genetic level. Clinicians should pay attention to patients with BPV combined with depressive disorders and develop timely interventions., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Air pollution is strongly associated with autoimmune diseases (ADs), however, the genetic causality between them remains poorly understood. Therefore, the aim of this study is to determine the relationship between common air pollutants and ADs through Mendelian randomization (MR) analysis. We conducted a MR study using aggregated data from publicly available genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) associated with 5 common air pollutants are used as instrumental variables. Random-effects inverse variance weighted (IVW) is used as the primary method to assess causal relationships, with results reported in terms of odds ratios (OR). In addition, we used a two-step MR to assess the mediating role of common risk factors for ADs in the effects of air pollution on ADs. Our analysis revealed causal associations between selected air pollutants and specific ADs. Exposure to nitrogen oxides was positively associated with the risk of rheumatoid arthritis (RA) (OR = 1.47,95% CI 1.01-2.14, P = 0.043), Sjogren's syndrome (SS) (OR = 2.29,95% CI 1.08-4.89, P = 0.032), and systemic lupus erythematosus (OR = 7.26,95% CI 2.25-23.40, P = 9.10E-04). Genetically predicted PM2.5 and PM10 were risk factors for ulcerative colitis (OR = 1.68,95% CI 1.05-2.68, P = 0.032) and psoriasis (OR = 1.34,95% CI 1.02-1.76, P = 0.037), respectively. Our results also suggest a negative causal relationship between PM2.5-10 and SS (OR = 0.29, 95% CI 0.10-0.90, P = 0.032). In risk factor-related mediation analyses, BMI and smoking mediated 6% (95% CI 1-10%) and 9% (95% CI 2-17%) of the effect of nitrogen oxides on RA, respectively. This study provides evidence of a causal relationship between air pollutants and specific ADs risks, suggesting that improving air pollution may be important in preventing ADs., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All the exposure and outcome data were released by previous studies that had passed the ethical review of institutional review boards (IRBs). This study does not require additional ethical review. Consent for publication: Not applicable., (© 2024. The Author(s).)

This study evaluated the causal relationship between matrix metalloproteinases (MMPs) and pulmonary embolism using data from the genome-wide association study (GWAS) of pulmonary embolism from the UK Biobank and a GWAS dataset of MMPs based on 5,457 Icelanders aged 65 years and older. MR-Egger, MR-PRESSO, Cochran's Q, and leave-one-out were used for sensitivity analysis. The Mendelian randomization (MR) analysis, based on the IVW analysis, indicated an elevated risk for pulmonary embolism in association with MMP19 (OR = 1.0009, 95%CI: 1-1.0017, P = 0.041), consistent with the weighted median method results (P = 0.015). In addition, despite the negative result from the IVW method (P = 0.554), the weighted median analysis suggested a reduced risk for pulmonary embolism related to MMP12 (OR = 0.9992, 95%CI: 0.9984-1, P = 0.038). No causal associations were found for the other MMPs (including MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP13, MMP14, MMP16, MMP17, and MMP20) on pulmonary embolism (all P > 0.05). The reverse MR analysis revealed no causal associations between pulmonary embolism as exposure and MMPs as outcomes. Sensitivity analyses confirmed the robustness of these findings. In conclusion, this MR analysis revealed the potential causal relationship between MMPs and pulmonary embolism, suggesting that measuring MMPs could help identify people at higher risk of pulmonary embolism, but further research is needed., Competing Interests: Declarations. Ethics approval and consent to participate: This article is a Mendelian randomization study. The data for this study were obtained from publicly available databases and published literature data and did not require ethical approval and written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

With the ongoing rise in the incidence of inflammatory bowel disease (IBD), its extraintestinal manifestations have garnered significant attention. IBD-related arthritis is notable for its insidious onset and unpredictability, presenting considerable challenges for clinical diagnosis and management. Factors such as gut microbiota, plasma proteins, inflammatory proteins, and biomarkers found in blood and urine may be closely associated with IBD-related arthritis. However, the mechanisms by which these factors influence this condition remain poorly understood and require urgent investigation. We employed the method of linkage disequilibrium and the two-sample Mendelian randomization (MR) approach, utilizing single nucleotide polymorphisms (SNPs) identified from large-scale genome-wide association studies as instrumental variables. In this scientifically rigorous manner, we explored the potential causal relationship between gut microbiota, plasma proteins, inflammatory proteins, and blood and urine biomarkers in relation to arthritis resulting from inflammatory bowel disease (IBD). This method aids in elucidating the potential roles of these biomarkers in the development of arthritis following IBD, while minimizing the confounding factors and reverse causality commonly encountered in observational studies. To further verify and strengthen our findings, we conducted subsequent sensitivity analyses. These analyses will evaluate the strength of the association between SNPs and the studied biomarkers, as well as post-IBD arthritis, while accounting for variations in SNP distribution among populations and other potential genetic influencing factors. Through these rigorous analytical steps, our objective is to enhance the robustness and credibility of the research findings and provide more reliable scientific evidence regarding the pathogenesis of post-IBD arthritis. MR analysis provides evidence for the association between genetically predicted gut microbiota, plasma proteins, inflammatory proteins, and blood and urine biomarkers with the risk of IBD-related arthritis. This analysis investigates the characteristics of the associations between specific gut microbiota, plasma proteins, inflammatory proteins, and blood and urine biomarkers in relation to IBD-related arthritis. Among the plasma proteins, pterin-4-alpha-carbinolamine dehydratase, aldo-keto reductase family 1 member C4, cathepsin L2, angiostatin, hepatocyte growth factor-like protein, hepatitis A virus cellular receptor 2, protein O-linked mannose beta-1,4-N-acetylglucosaminyltransferase 2, epididymal-specific alpha-mannosidase, and platelet-derived growth factor receptor-like protein are associated with Crohn's disease-related arthritis. In contrast, agrin, methylenetetrahydrofolate synthetase domain-containing protein, neurotrophin-3 (NT-3) growth factor receptor, and neuropilin-1 are associated with ulcerative colitis-related arthritis. Furthermore, regarding gut bacterial pathway abundance, adenosylcobalamin, N-acetylglucosamine, N-acetylmannosamine, and N-acetylneuraminic acid degradation, as well as glycolysis metabolism and degradation pathways, are associated with Crohn's disease-related arthritis. Meanwhile, gut bacterial pathway abundance (pentose phosphate pathway) and gut microbiota abundance (Bacteroidetes, Bacteroidia, Bacteroidales, Porphyromonadaceae, Faecalibacterium, Eubacterium eligens) are linked to ulcerative colitis-related arthritis. Notably, we did not identify any connections between inflammatory protein factors, blood and urine biomarkers, and IBD-related arthritis. Lastly, in the reverse MR study, the insufficient number of SNPs available for analysis precluded the detection of a reverse causal relationship. This study employs the MR method to elucidate the potential causal relationships among gut microbiota, plasma proteins, inflammatory proteins, and blood and urine biomarkers in relation to the occurrence and progression of IBD-related arthritis. This research offers a novel perspective for a deeper understanding of the pathogenesis of IBD-related arthritis and highlights future directions for the diagnosis and treatment strategies of this condition., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to Participate: In this study, all GWAS data are sourced from previously published statistical analyses, thereby eliminating the necessity for additional ethical approval., (© 2024. The Author(s).)