Two-sample Mendelian Randomization Analysis Research Articles

Metabolic abnormalities, liver enzymes increased risk of gallstones: a cross-sectional study and multivariate mendelian randomization analysis.

Some studies have explored the relationship between metabolic abnormalities, elevated liver enzymes and gallstone risk, but the results have been inconsistent. The aim of this study was to comprehensively assess the relationship between metabolic abnormalities, liver enzymes, and gallstone risk through a cross-sectional study and Mendelian randomization analysis. Firstly, a cross-sectional study was conducted involving 555,31 subjects who underwent physical examinations at the Second Affiliated Hospital of Xi'an Jiaotong University between January 2021 and December 2021. The diagnosis of gallstones was based on ultrasound findings. Multivariable logistic regression analysis was employed to investigate the associations between metabolic abnormalities, liver enzymes, and the risk of gallstones. Additionally, two-sample and multivariate Mendelian randomization analyses were performed to further explore the genetic causal associations. In the cross-sectional analysis, the detection rate of gallstones was 4.8%, showing a gradual increase with age and BMI (body mass index) in both men and women. Gallstones were found to be comorbid with various metabolic disorders and were associated with elevated liver enzymes. Multivariate analysis showed that female sex, age, body mass index, diastolic blood pressure, fatty liver, alanine aminotransferase, and gamma-glutamyltransferase may be independent risk factors for gallstones, whereas high-density lipoprotein cholesterol may be a protective factor. Two-sample and multivariate Mendelian randomization analyses further revealed a causal association between genetically predicted BMI, type 2 diabetes mellitus, alanine aminotransferase, gamma-glutamyl transferase, and an increased risk of gallstones. The findings suggest that metabolic abnormalities and elevated liver enzymes may increase the risk of developing gallstones.

Association of Visceral Adipose Tissue With Hypertension: Results From the NHANES 2011-2018 and Mendelian Randomization Analyses.

The causal relationship between visceral adipose tissue (VAT) and hypertension remains unclear. We aimed to examine the potential association between them using observational and two-sample Mendelian randomization (MR) analyses. Data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were used, applying multivariable logistic regression analysis to investigate the association between VAT mass and hypertension risk. Independent genetic variants related to VAT mass were derived from genome-wide association studies (GWAS) in 325 153 UK Biobank participants. The primary analysis employed the random-effects inverse-variance weighted (IVW) method, with MR-Egger, weighted median, simple mode, and weighted mode as sensitivity analyses. A total of 7661 participants were included. After adjusting for confounding factors, increased VAT mass was associated with a higher risk of hypertension (quartile 4vs. quartile 1: OR:1.85, 95% confidence intervals [CI]: 1.31-2.63). Furthermore, VAT mass exhibited greater accuracy than body mass index (BMI) in predicting hypertension (areas under the curve [AUC]: 0.701vs. 0.676, p for comparison < 0.001). The MR analyses demonstrated a causal relationship between increased VAT mass and the risk of hypertension in primary analyses (odds ratio [OR]:1.768, 95% CI: 1.594-1.861). Consistent findings across various MR models substantiate the robustness and strength of this causal relationship. These analyses provide additional support for both the positive association and causal relationship between elevated VAT and the risk of developing hypertension, suggesting that targeted interventions for VAT may be beneficial in preventing hypertension.

Skin Microbiota and Pathological Scars: A Bidirectional Two-Sample Mendelian Randomization Study.

Pathological scars (PSs), resulting from abnormal skin repair, chronic inflammation, and fibrosis, affect millions of people. Previous studies have demonstrated that skin microbiota (SM) plays a role in cutaneous inflammation and healing, but the interplay between PSs and SM remains unclear yet. To investigate the causal associations between SM and two specific PSs: hypertrophic scars (HSs) and keloids. A bidirectional two-sample mendelian randomization (MR) analysis using genetic data for SM, HS, and keloids was conducted. The random-effects inverse variance weighted (IVW) method was used as the primary approach, along with multiple MR methods. False discovery rate (FDR) correction was employed to address multiple testing. In forward analysis, the family Moraxellaceae and order Pseudomonadales exhibited the same significant protective effects on keloids (odds ratio [OR]: 0.849, 95% confidence interval [CI]: 0.770-0.935, q2 = 0.03626). The class Betaproteobacteria (OR: 0.938, 95% CI: 0.894-0.985, q1 = 0.01965) and genus Bacteroides (OR: 0.928, 95% CI: 0.884-0.973, q1 = 0.00889) each demonstrated a suggestive protective effect on HSs and keloids, respectively. Some limited evidence suggested that order Actinomycetales contributes to an increased risk of keloids. In reverse analysis, keloids were found to have negative effects on the class Gammaproteobacteria with limited evidence. There was no detectable evidence of horizontal pleiotropy or heterogeneity. This study provided evidence for the causalities between SM and PSs, which laid foundation for furthering clinical practice and research of microorganism-skin interaction.

Elevated thyroid-stimulating hormone levels, independent of Hashimoto's thyroiditis, increase thyroid cancer risk: Insights from genetic and clinical evidence.

Hashimoto's thyroiditis (HT) is a prevalent autoimmune disorder and thyroid cancer (TC) is the most prevalent endocrine malignancy. Recent debates have focused on whether HT increases the risk of developing TC. This study combined Mendelian randomization (MR) and observational methods to investigate the potential causal relationship between HT and TC risk. First, we performed two-sample MR and multivariable MR (MVMR) analysis using the genome-wide association studies (GWAS) data from multiple databases, including European and East Asian populations, to estimate the effect of HT and thyroid-stimulating hormone (TSH) levels on TC risk. Second, we conducted an observational study using data from the National Health and Nutrition Examination Survey (NHANES) database and evaluated the association between HT, TSH, and TC prevalence through logistic regression model and restricted cubic spline model. Our MR findings revealed no significant association between HT and TC risk in both populations. However, elevated TSH levels significantly increased TC and papillary thyroid carcinoma (PTC) risk, while lower TSH levels were associated with reduced TC risk. Further MVMR analysis and an observational study confirmed this. Additionally, our observational study also indicated no significant relationship between HT and TC prevalence and abnormal TSH levels correlated with higher TC risk. HT was not a TC risk factor, but high TSH levels increased TC risk. Controlling TSH within normal ranges through thyroid hormone replacement was recommended to reduce TC risk in HT patients with elevated TSH levels, even those without symptoms.

Causal association between depression and constipation: A bidirectional two-sample Mendelian randomization study.

There is currently insufficient research on the causal relationship between depression and constipation. This study aims to provide clear evidence for the positive and negative causal relationship between depression and constipation through bidirectional two-sample Mendelian randomization (MR) analysis. MR is a statistical method used to evaluate the credible causal relationship between exposure and outcomes. In this study, we extracted corresponding genetic data from independent cohorts of patients with depression and constipation. Depression data was obtained from the Finngen database, while constipation data was obtained from the IEU OPEN genome-wide association study database. MR analysis was conducted using 5 methods: inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode. In addition, we also used Cochran Q test, MR-Egger intercept test, and leave-one-out analysis to test for the existence of horizontal pleiotropy and evaluate the robustness of MR analysis results. In the analysis of the impact of depression on constipation, we identified 15 significant and statistically strong single nucleotide polymorphisms, and the IVW random effects analysis showed a causal relationship (OR = 1.005 [1.003, 1.007], P = 1.26 × 10-5). When analyzing the impact of constipation on depression, 10 significant and statistically strong single nucleotide polymorphisms were identified, but IVW analysis did not find a causal relationship (OR = 73.768 [0.004, 1.306 × 10-6], P = .389). There is no heterogeneity in the impact of depression on constipation in the bidirectional analysis results, and there is heterogeneity in the impact of constipation on depression, but there is no horizontal pleiotropy. Our bidirectional two-sample MR analysis identified a causal relationship between depression and constipation. This discovery may help clinical doctors to intervene in depression patients in a timely and effective manner when treating constipation patients, avoiding further deterioration of the condition.

Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.

To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach. Additionally, different GWAS summary data for NDDs were used to validate the initial results and perform sensitivity analyses to enhance the robustness of the findings. Finally, reverse MR analyses were conducted to assess the possibility of reverse causation. Combining results from the initial and replication phases of MR analysis, we identified potential causal relationships between various CSF metabolites and different NDDs. Specifically, we found potential causal relationships between five CSF metabolites and AD, six CSF metabolites and MS, and thirteen CSF metabolites and ALS. Further sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis indicated causal effects of AD on glucuronate and ALS on acetylcarnitine (C2). Our study, through genetic means, demonstrates close causal associations between the specific types of CSF metabolites and the risk of NDDS (AD, PD, MS, and ALS), providing useful guidance for future clinical researches.

Causality between gut microbiota, immune cells, and breast cancer: Mendelian randomization analysis.

The association between gut microbiota (GM) and breast cancer (BC) has been studied. Nevertheless, the causal relationship between them and the potential mediating factors have not been clearly defined. Therefore, in this study, Mendelian randomization analysis (MR) was employed to explore the causal relationship between 473 GM and BC, as well as the mediating effect of potential immune cells. In this investigation, we availed ourselves of the publicly accessible summary statistics from the genome-wide association study to undertake two-sample and reverse Mendelian randomization analyses on GM and BC, with the intention of clarifying the causal association between GM and BC. Subsequently, through the application of the two-step Mendelian randomization analysis, it was revealed that the relationship between GM and BC was mediated by immune cells. The stability of the research outcomes was verified via sensitivity analysis. Mendelian randomization analysis elucidated the protective impacts of 8 genera on BC (such as Phylum Actinobacteriota, Species Bacteroides A plebeius A, Species Bifidobacterium adolescentis, Species CAG-841 sp002479075, Family Fibrobacteraceae, Order Fibrobacterales, Class Fibrobacteria, and Species Phascolarctobacterium sp003150755). Additionally, there are 23 immune cell traits related to BC. Our research findings showed that the species Megamonas funiformis was associated with an increased risk of BC, and 11.20% of this effect was mediated by CD38 on IgD+ CD24-. Likewise, HLA DR on CD33br HLA DR+ CD14- mediated the causal relationship between Species Prevotellamassilia and BC, having a mediating ratio of 7.89%. This study clarifies a potential causal relationship between GM, immune cells, and BC and provides genetic evidence for this causal connection. It offers research directions for the subsequent prevention and treatment of BC through the interaction between GM and immune cells, and provides a reference for future mechanistic and clinical studies in this field.

Causal association between cholecystectomy and fracture: A Mendelian randomization study.

Previous observational studies have reported that cholecystectomy is associated with an increased risk of fracture. However, the causality of this association remains unclear. This study aimed to explore the causal relationship between cholecystectomy and fracture using a Mendelian randomization (MR) approach. Our primary analytical method was the comprehensive two-sample MR analysis, with inverse variable weighting (IVW) serving as the main analysis technique. In addition, we use Bayesian weighted MR analysis to further confirm the results of IVW method. To enhance the robustness of our findings, we employed multiple analytical approaches including MR-Egger, weighted mode, simple mode, and weighted median. We further conducted sensitivity analyses to validate the stability and feasibility of our dataset. The results of IVW methods showed that there had no significant causal effect of cholecystectomy on fracture (forward P value: .82, .63, .96, .60, .19, .40, .58, .38, .37, .97, and .50 for fracture of wrist and hand, fracture of femur, fracture of foot, fracture of forearm, fracture of lower leg, fracture of lumbar spine and pelvis, fracture of neck, fracture of ribs, fracture of shoulder and upper arm, fracture of skull and facial bones, and fracture of spine), the results of Bayesian weighted MR showed similar results (P > .05). In the reverse, fracture of femur (P = .01) and fracture of shoulder and upper arm (P = .01) showed increased risks of cholecystectomy. The sensitivity analysis showed that none of our analyses were horizontally pleiotropic (P > .05 for MR-Egger's intercept method). Our results do not support the causal effect of cholecystectomy on fracture, which was opposite to most previous observational studies.

Causal relationship between physical activity and scoliosis: A Mendelian randomization study.

Scoliosis, marked by abnormal spinal curvature, is common in adolescents and can lead to chronic pain and reduced quality of life. The relationship between physical activity and scoliosis is debated. In this study, we aim to investigate the causal relationship between physical activity levels and idiopathic scoliosis risk using the Mendelian randomization (MR) approach. Two-sample MR analyses evaluated low-intensity (low-intensity physical activity [LIPA]), moderate-to-vigorous (MVPA), and total physical activity (TLA) as exposures, selecting genetic instruments based on their associations. Total physical activity significantly associated with idiopathic scoliosis (OR = 1.72; 95% CI = 1.11-2.68; P = .015), whereas LIPA and MVPA showed no significant associations. Reverse MR found no idiopathic scoliosis impact on activity levels. Multivariable MR showed no significant activity-scoliosis links. Total physical activity emerges as an idiopathic scoliosis risk factor, warranting mechanistic exploration. LIPA and MVPA do not causally link to scoliosis. Idiopathic scoliosis does not influence activity levels.

Genetic insights into the roles of fatty acids and gut microbiota in osteoarthritis: A Mendelian randomization study.

Traditional observational studies have shown that fatty acids and gut microbiota are crucial in osteoarthritis (OA) progression, but their findings are often conflicting due to biases, confounding factors, and measurement errors. We conducted a two-sample Mendelian randomization analysis using genome-wide association study data on fatty acids from 136,016 individuals, the gut microbiota from 7738 individuals, and osteoarthritis from 314,870 individuals. Elevated levels of total (odds ratio [OR]: 0.92; 95% CI 0.84-1.00; P = .039), saturated fatty acids (OR: 0.91; 95% CI 0.84-0.99; P = .034), and linoleic acid (OR: 0.92; 95% CI 0.85-1.00; P = .040) were associated with reduced OA risk. In terms of gut microbiota, Bifidobacterium adolescentis (OR: 0.89; 95% CI 0.80-1.00; P = .048) and Escherichia (OR: 0.90; 95% CI 0.81-1.00; P = .042) demonstrated protective roles against OA. Conversely, Oscillibacter (OR: 1.16; 95% CI 1.00-1.34; P = .043), Bilophila (OR: 1.28; 95% CI 1.07-1.54; P = .007), Erysipelotrichaceae (OR: 1.08; 95% CI 1.00-1.16; P = .044), and Bilophila within the Desulfovibrionaceae family (OR: 1.19; 95% CI 1.04-1.36; P = .012) were associated with an increased risk of OA. The findings indicate that modulating dietary factors and gut microbiota can independently reduce the risk and progression of OA, potentially improving the quality of life and health management in aging populations.

Dietary factors and rheumatoid arthritis: new perspectives from a Mendelian randomization analysis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease, and there is growing evidence suggesting a potential correlation between dietary factors and the pathogenesis of this condition. In order to investigate the causal relationship between diet and RA, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal associations between 22 dietary factors and RA. Summary data from genome-wide association studies (GWAS) of RA were obtained from large GWAS meta-analyses. GWAS summary data for 22 dietary factors were obtained from UK Biobank (UKB). Random-effects inverse variance weighted (IVW) was used as the primary method for assessing causality, and analyses of heterogeneity and horizontal pleiotropy were performed to ensure the accuracy of the results. Research indicates a negative genetic causal relationship between cereal intake (OR = 0.64, 95% CI: 0.41 - 0.99, P = 0.048) and oily fish intake (OR = 0.70, 95% CI: 0.52 - 0.95, P = 0.020) with the risk of RA. Other dietary factors were not causally related to RA. Sensitivity analysis shows that our results are reliable. This study provides genetic evidence suggesting that cereal intake and oily fish intake are protective factors for RA, indicating that RA patients and individuals at high risk should make appropriate dietary adjustments.

Identification of Circulating Proteins Associated With Blood Pressure.

Circulating proteins in blood are involved in various physiological processes, but their contributions to blood pressure regulation remain partially understood. In traditional observational studies, identifying circulating proteins causally associated with blood pressure is challenging because of potentially unmeasured confounding and possible reverse causality. Two-sample Mendelian randomization analyses were conducted to estimate the causal effects of 2270 circulating proteins (data sourced from 8 genome-wide association studies) on diastolic blood pressure, systolic blood pressure, and pulse pressure. Colocalization analyses were then used to investigate whether the circulating proteins and blood pressure traits shared causal genetic variants. To further verify the findings, we subsequently performed Steiger filtering analyses, annotation of protein-altering variants, assessment of overlap between protein quantitative trait loci and expression quantitative trait loci, protein-protein interaction and functional enrichment analyses, and drug target evaluation. To provide more potential biomarkers, we further evaluated the epidemiological associations of 2923 circulating proteins with blood pressure and hypertension by cross-sectional and longitudinal analyses using individual data in the UK Biobank. Mendelian randomization and colocalization analyses identified 121 circulating proteins with putative causal effects on at least 1 blood pressure trait. Many of the identified proteins are enriched in the pathways relevant to blood pressure regulation, and a majority of these proteins are either known drug targets or druggable candidates. This study has uncovered numerous circulating proteins potentially causally associated with blood pressure, providing insights into the regulatory mechanisms of blood pressure and potential therapeutic targets to facilitate blood pressure management.

Unraveling the causal associations between systemic cytokines and six inflammatory skin diseases

BackgroundPrevious observational studies have reported that systemic cytokines are associated with the risk of inflammatory skin diseases, but their conclusions remain controversial. MethodWe conducted a two-sample Mendelian randomization analysis to assess the relationship between systemic cytokines and six inflammatory skin disorders (including alopecia areata (AA), acne, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis (PS) and vitiligo), based on datasets from EArly Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium, acne GWAS conducted by Maris Teder Laving et al., IEU Open GWAS, and FinnGen database. Inverse-variance weighted (IVW) method was conducted in primary MR analysis, and supplemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO. ResultsBy integrating the findings from both primary and sensitivity analyses, we identified ten systemic cytokines linked to the risk of six skin diseases using the IVW method. Briefly, four cytokines increased the risk of corresponding skin diseases: β-nerve growth factor (β-NGF) to AA (p = 0.005) and HS (p = 0.001), interleukin-8 (p = 0.014) to acne; interleukin-5 (p = 0.042) to AD; interleukin-13 (p = 0.049) to PS. In the meantime, seven cytokines could have protective effect on specific skin diseases: interleukin-9 (p = 0.040) and interleukin-2 receptor subunit alpha (IL-2ra) (p = 0.020) on AA; macrophage inflammatory protein (MIP)-1β (p = 0.020) on acne; monokine induced by IFN-γ (p = 0.006) on AD; interleukin-16 (p = 0.038), MIP-1β (p = 0.017) and IL-2ra (p = 0.020) on PS. ConclusionsThis study reveals 13 causal associations between systemic cytokines and 6 skin diseases, offering new perspectives on the prevention and management of widespread inflammatory skin disorders.

Antioxidants and the risk of metabolic dysfunction-associated steatotic liver disease: results of National Health and Nutrition Examination Survey and two-sample Mendelian randomization analyses

Background The link between antioxidants and metabolic dysfunction-associated steatotic liver disease (MASLD) is a topic of considerable discussion in the field of observational studies, with the exact causal connections still being unclear. Methods In this investigation, a cohort consisting of 17 061 participants from the National Health and Nutrition Examination Surveys was studied. Initially, a cross-sectional analysis was carried out to examine the relationship between the CDAI and MASLD. Further, Mendelian randomization (MR) was utilized to assess the possible causal links between antioxidant levels in the bloodstream and MASLD. Results The association between the CDAI and MASLD was found to be significant in the fully adjusted logistic regression model, showing an OR of 0.95 [95% confidence interval (CI): 0.94–0.97; P &lt; 0.001]. The use of restricted cubic spline regression revealed no significant nonlinear association between the CDAI and the occurrence of MASLD (P nonlinearity = 0.321). Additionally, MR findings did not suggest any causal connections between circulating levels of various antioxidants and MASLD. These antioxidants included vitamin A (retinol) (IVW: OR: 0.67, 95% CI: 0.33–1.36, P = 0.272), vitamin C (ascorbate) (IVW: OR: 0.61, 95% CI: 0.34–1.09, P = 0.094), vitamin E (α-tocopherol) (IVW: OR: 0.55, 95% CI: 0.13–2.25, P = 0.407), vitamin E (γ-tocopherol) (IVW: OR: 0.89, 95% CI: 0.36–2.23, P = 0.806), zinc (IVW: OR: 0.95, 95% CI: 0.82–1.09, P = 0.449), selenium (IVW: OR: 0.98, 95% CI: 0.84–1.16, P = 0.855), and carotene (IVW: OR: 0.80, 95% CI: 0.36–1.81, P = 0.596). Conclusion The findings highlight a significant negative linear relationship between CDAI and MASLD prevalence in the observational component of the study. However, the MR analysis did not indicate any causal effects of circulating antioxidant levels on MASLD.

The genetic causal association between arthritis and low back pain.

Arthritis and low back pain (LBP) are prevalent musculoskeletal conditions with a perceived association. Previous observational studies have suggested a possible link between arthritis and LBP, but causality has not been firmly established. The analysis involved data from a meta-analysis of genome-wide association studies sourced from the UK Biobank Genetics resources on rheumatoid arthritis (RA), osteoarthritis (OA) at any site, knee osteoarthritis (KOA), hip osteoarthritis (HOA), and LBP. Two-sample Mendelian randomization analysis was utilized to evaluate the causal link between arthritis and LBP. The primary method employed was inverse-variance weighting (IVW), with additional techniques such as MR-Egger, weighted median, Cochran Q statistic, and leave-one-out analysis used to identify heterogeneity and pleiotropy. Genetically determined RA exhibited a causal impact on LBP (Weighted median: odds ratio [OR] = 1.094, 95% confidence interval [CI] 1.002-1.195, p = 0.043). Furthermore, OA at any site and KOA showed causal associations with LBP (Inverse variance weighted: OR = 1.089, 95% CI 1.011-1.173, p = 0.026) and (OR = 1.0004, 95% CI 1.000-1.008, p = 0.019), respectively. Additionally, HOA was also linked causally with an elevated risk of developing LBP (Weighted median: OR = 1.002, 95% CI 1.000-1.004, p = 0.049; Inverse variance weighted: OR = 1.002, 95% CI 1.001-1.004, p = 0.003). This study offers genetic evidence supporting the causal relationship between RA, OA at any site, KOA, HOA and the increased risk of LBP, especially highlighting the significant impact of HOA.

Causal association between glaucoma and risk of retinal vascular occlusion: a Mendelian randomization study.

Retinal vein occlusion (RVO) leads to visual impairment, and risk factors may include glaucoma. Although some studies suggest a relationship between glaucoma and RVO, it is unknown whether this association is causal. We performed Mendelian randomization (MR) analyses to evaluate the causal contribution to RVO of five genetically predicted glaucoma conditions. We conducted two-sample univariable MR analysis using inverse variance weighting, weighted median, and MR-Egger methods. We obtained publicly available datasets of genome-wide association studies (GWAS) meta-analyses for glaucoma as the exposure and a GWAS for RVO in the Finn Gen biobank study as the outcome. Genetically predicted glaucoma was causally associated with RVO risk (beta = 0.267, standard error [SE] = 0.052, odds ratio [OR] = 1.306, 95% confidence interval [CI]: 1.181-1.445). This association was supported by sensitivity analyses using weighted median (beta = 0.211, SE = 0.075, OR = 1.235, 95% CI: 1.067-1.429), weighted mode (beta = 0.491, SE = 0.132, OR = 1.633, 95% CI: 1.261-2.116), and MR-Egger (beta = 0.3900, SE = 0.138, OR = 1.476, 95% CI: 1.128-1.933) methods. MR analyses using the validation dataset obtained consistent results. Our results indicated that glaucoma is likely causally associated with an increased risk of RVO. The current findings may help in determining the underlying mechanisms via which glaucoma affects the risk of RVO.

Genetic insights into kidney stone formation: a Mendelian randomization study of protein quantitative trait loci.

Kidney stones are a common urological condition caused by a complex interaction of genetic, metabolic, and environmental factors. Recent genomic research has shed light on the genetic basis of kidney stone susceptibility.This study aims to identify protein quantitative trait loci (pQTL) associated with kidney stone formation and explore their causal relationships using Mendelian randomization.We conducted two-sample Mendelian Randomization (MR) analyses utilizing Genome-Wide Association Study (GWAS) summary data to assess the causal impact of pQTL on kidney stone formation. Data sources included the UK Biobank dataset "ukb-b-8297" and an external validation dataset "ukb-b-13537". We employed inverse variance weighting (IVW) as the primary MR method, supplemented by sensitivity analyses such as MR-PRESSO, Leave-One-Out, and Cochran Q tests to validate the robustness of our findings.Our analyses identified significant associations between several pQTL and kidney stones. Key proteins such as CD27, CXCL9, and TNFRSF1A exhibited significant centrality in the protein-protein interaction (PPI) network, suggesting their critical roles in kidney stone pathogenesis. The KEGG pathway enrichment analysis revealed significant pathways, including cytokine-cytokine receptor interaction and osteoclast differentiation, highlighting the involvement of immune response and inflammatory processes in kidney stone formation.This study underscores the significance of pQTL in kidney stone research, identifying key proteins and pathways that may serve as biomarkers or therapeutic targets. The findings provide insights into the genetic and molecular mechanisms underlying kidney stone formation, offering potential avenues for future research and therapeutic interventions.

Causal association of serum vitamin D levels with urolithiasis: a bidirectional two-sample Mendelian randomization study.

In light of inconsistent evidence from previous observational studies regarding the correlation between serum vitamin D levels and urolithiasis, this study aimed to investigate the genome-wide causal association between genetically predicted serum 25(OH)D levels and urolithiasis using the Mendelian randomization (MR) approach. In this study, we utilized genome-wide association studies (GWAS) summary statistics from the UK Biobank and SUNLIGHT consortium for serum vitamin D levels, as well as urolithiasis data from FinnGen. We employed bidirectional two-sample MR analysis to evaluate potential causal relationships. The primary MR analysis relied on the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode approaches. Sensitivity analyses were conducted to ensure result robustness, including Cochran's Q test, MR-Egger intercept test, leave-one-out tests, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. The MR analysis indicated no significant causal effects of serum 25(OH)D levels on urolithiasis [IVW method: (kidney and ureteral stones: OR = 1.134;95% CI, 0.953 to 1.350, p = 0.155; lower urinary tract stones: OR = 1.158; 95% CI, 0.806 to 1.666, p = 0.428)]. However, according to the IVW results, genetically predicted kidney and ureteral stones were associated with decreased serum 25(OH)D levels (beta = -0.025; 95% CI, -0.048 to -0.003; p = 0.028), while they did not indicate a causal effect of lower urinary tract stones on serum 25(OH)D levels (beta = -0.002; 95% CI, -0.013 to -0.008; p = 0.662). A sensitivity analysis suggested the robustness of these causal associations. Our MR study did not provide evidence supporting a causal association between serum 25(OH)D levels and urolithiasis among individuals of European descent. However, there might exist a negative causal association between kidney and ureteral stones and serum 25(OH)D levels.

Causal association between epigenetic age acceleration and two pulmonary vascular diseases: pulmonary arterial hypertension and pulmonary embolism—a bidirectional Mendelian study

BackgroundPulmonary arterial hypertension (PAH) is a relatively rare but severe disease with a poor prognosis. Pulmonary embolism (PE) is a serious condition that can cause sudden death. Epigenetic age acceleration (EAA) is a robust indicator derived from the DNA methylation-based epigenetic clock, which can predict the extent of aging. It has been proved that the epigenetic clock and EAA are associated with many cardiovascular diseases, while their associations with PAH and PE remain inconclusive. Our study aims to investigate the associations among these factors.MethodBy harnessing summary-level data from large-scale genome-wide association studies (GWAS), we designed a two-sample bidirectional Mendelian randomization (MR) analysis to assess the causal associations between measures of three epigenetic clocks, including GrimAge acceleration (n = 34,467), Hannum Age acceleration (n = 34,449) and PhenoAge acceleration (n = 34,463) and PAH (including 125 cases and 162,837 controls), as well as PE (including 3940 cases and 480,658 controls). The inverse variance-weighted (IVW) method was used as the primary method for MR analysis. Other methods, such as MR egger and weighted mode, served as complements to the IVW approach, were also applied in the analyses. Then, the MR pleiotropy test and MR-PRESSO test, which are effective tools for quality control of MR analysis, were subsequently used to ensure the accuracy of the study.ResultsThe forward MR analysis indicated that all three epigenetic clocks had no significant effects on PAH or PE. The reverse analysis indicated that the onset and progression of PAH and PE had insignificant effects on three epigenetic clocks. The results of the quality control assessment confirmed that our findings were reliable.ConclusionOur two-sample bidirectional MR analysis suggested that there is no significant association between epigenetic clocks and these two pulmonary vascular diseases.

Exploring the relationship between air pollution, non-alcoholic fatty liver disease, and liver function indicators: a two-sample Mendelian randomization analysis study

Exploring the relationship between air pollution, non-alcoholic fatty liver disease, and liver function indicators: a two-sample Mendelian randomization analysis study