Mendelian Randomization Approach Research Articles

Gut microbiota may mediate the causality of statins on diabetic nephropathy: a mediation Mendelian randomization study.

Increasing evidence indicates that statins may increase the risk of developing diabetic nephropathy (DN). As the gut-kidney axis concept gains traction, it remains unclear whether statins contribute to the onset and progression of DN by modulating gut microbiota. To investigate the association between statins and DN and the proportion of this association mediated through gut microbiota. This study utilized a two-sample Mendelian randomization (MR) approach and a cross-sectional observational design to investigate the causal relationships among statins, 473 gut microbiota, and DN. Furthermore, mediation MR analysis was employed to explore the potential mediating effects of gut microbiota in the statins-DN relationship. HMGCR inhibitors were causally linked to the increased incidence of DN (odds ratio [OR]: 0.732, 95% confidence interval [CI] 0.647, 0.828, PFDR = 0.000004). Supporting results from a cross-sectional study based on the Medical Information Marketplace in Intensive Care (MIMIC-IV) database also indicated this association (OR: 0.74, 95% CI: 0.61, 0.91, P = 0.004). Among the 473 identified gut microbiota species, 13 (PFDR < 0.05) were causally associated with DN. The mediation MR analysis revealed that 10 gut microbiota mediated the relationship between statins and DN, acting as either protective or risk factors (P < 0.05). In addition, HMGCR and related proteins may be involved in lipid metabolism, insulin resistance, and AMPK signaling pathway. Statins may become a risk factor for DN by increasing or decreasing the abundance of specific gut microbiota. These specific gut bacteria have the potential to become a new indicator for guiding the clinical use of statins in diabetic patients.

Metabonomic Biomarkers of Plaque Burden and Instability in Patients With Coronary Atherosclerotic Disease After Moderate Lipid-Lowering Therapy.

Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid-lowering therapy. We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid-lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2-sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow-up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low-density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low-density lipoprotein cholesterol marker. In large high-density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score-based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018-1.295]) independent of demographic factors, medication use, and disease status. Our findings highlight the potential of nuclear magnetic resonance-based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.

The role of omega-3 fatty acids in acute pancreatitis.

Prior observational studies have reported the potential protective effect of omega-3 fatty acids on the prognosis of acute pancreatitis. However, the causal impact of omega-3 fatty acids on acute pancreatitis is unclear. We aimed to investigate further the association of omega-3 fatty acids with acute pancreatitis. We performed a meta-analysis and Mendelian randomization (MR) to explore the association between omega-3 fatty acids and the prognosis of acute pancreatitis from clinical observation and genetics perspectives, respectively. 9 randomized controlled trials were included in this study. The result meta-analysis showed that complementary therapy of omega-3 fatty acids significantly decreased mortality (RR: 0.30; 95% CI 0.14 to 0.65, P＜0.05) and infectious complications in acute pancreatitis (RR: 0.45; 95% CI 0.27 to 0.77, P＜0.05). Compared to the control groups, the hospital stays (MD: -1.02; 95% CI -1.85 to -0.20, P＜0.05) in acute pancreatitis patients with omega-3 fatty acids treatment were statistically reduced. However, the ICU stay (MD: -0.49; 95% CI -1.29 to -0.31, P＞0.05) between control groups and acute pancreatitis patients with omega-3 fatty acids treatment was insignificant. Utilizing genetic susceptibility analysis in the Mendelian randomization (MR) approach, the MR showed omega-3 fatty acids have a significant causal effect on the acute pancreatitis risk (OR, 0.887; 95% CI, 0.797-0.986, P = 0.027, fixed-effect; OR, 0.887; 95% CI, 0.792-0.993, P = 0.037, random-effect). Omega-3 fatty acids complementary therapy may improve the prognosis of acute pancreatitis. Furthermore, genetically predicted serum levels of omega-3 fatty acids can significantly lower acute pancreatitis risk.

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.

Multiple thyroid disorders and risk of osteoporosis: a two-sample Mendelian randomization study.

Previous research has demonstrated that even minor changes in thyroid function are associated with an increased risk of osteoporosis (OP). However, the causal relationship between thyroid disorders and the development of OP remains unclear. To address this, we aim to investigate the connection between genetic predispositions to various thyroid disorders and OP using a two-sample Mendelian randomization (MR) approach. Instrumental variables (IVs) for multiple thyroid disorders were sourced from a large genome-wide association study (GWAS) meta-analysis dataset. Summary-level data for OP were obtained from the FinnGen consortium. Inverse variance weighting (IVW) methods served as the primary approach for MR analysis. Sensitivity analyses included MR-Egger regression, heterogeneity testing, multiple validity tests, and leaFve-one-out sensitivity tests. IVW analysis revealed a direct causal effect of hypothyroidism (OR = 1.105, 95% CI 1.023-1.194, P 0.011) and Hashimoto's thyroiditis (OR = 1.142, 95% CI 1.026-1.271, P 0.015) on OP. However, no direct causal association was found between hyperthyroidism (OR = 1.030, 95% CI 0.944-1.123, P 0.508) or thyroid cancer (OR = 0.971, 95% CI 0.898-1.051, P 0.469) and OP. Our MR analysis revealed a causal association between hypothyroidism, Hashimoto's thyroiditis, and OP. This highlights the significant impact of thyroid function on bone health. However, further longitudinal studies are needed to confirm these findings conclusively.

Exploring the relationship between gut microbiota, immune characteristics, and female genital tract polyps using genetic evidence.

The study investigates the causal relationship between gut microbes and female genital tract polyps, exploring the potential mediating role of immune cells via Mendelian randomization (MR) analysis. Our MR study was designed following the STROBE-MR guidelines. We combined data from a large-scale GWAS meta-analysis, including 731 immune profiles and female genital tract polyps, with gut microbiology data sourced from the MiBioGen consortium. Univariate Mendelian randomization was employed to identify gut microbes and immune profiles significantly associated with female genital tract polyps causally. A 2-step MR analysis was utilized to investigate the potential mediating role of immune cells. Furthermore, we utilized the multivariable MR approach based on Bayesian model averaging (MR-BMA) to further assess the prioritization of gut microbiota vs immune characteristics in the development of female genital tract polyps. Through univariate MR analysis, we identified a significant causal link between 12 gut microbiota, 31 immune features, and female genital tract polyps. Four causal pathways involving gut microbiota, immune cells, and polyps were identified among them. MR-BMA analysis indicated marginal inclusion probability (MIP) values exceeding 0.1 for 5 gut microbiota groups: Victivallaceae (model-averaged causal estimate [MACE] = 0.060, MIP = 0.581, P = .0089), Ruminococcus gautreuii (MACE = 0.052, MIP = 0.346, P = .0640), Lachnoclostrium (MACE = 0.0380, MIP = 0.225, P = .1875), Alphaprobacter (MACE = 0.0186, MIP = 0.140, P = .3934), and Fusicatenibacter (MACE = 0.013, MIP = 0.110, P = .5818). Six immune features exhibit high priority, with MIP values exceeding 0.5, including HLA DR on CD33+ HLA DR+ CD14dim (MACE = -0.015, MIP = 0.753, P = .0853), HVEM on naive CD4+ T cell (MACE = 0.024, MIP = 0.737, P = .0053), CD80 on CD62L+ plastic cytoplasmic dendritic cell (MACE = 0.024, MIP = 0.721, P = .0228), CD28 on activated and secret CD4 regulatory T cell (MACE = 0.0054, MIP = 0.706, P = .3245), HLA DR on CD14+ CD16 monocyte (MACE = -0.0003, MIP = 0.520, P = .7927), HLA DR on CD14+ monocyte (MACE = -0.0029, MIP = 0.509, P = .5576). Our research indicates that gut microbiota exerts an independent causal influence on female genital tract polyps, potentially impacting them via various immune cells.

Bone biochemical markers, bone mineral density, and the risk of osteonecrosis of the femoral head: a Mendelian randomization study

BackgroundAlterations in bone metabolism may play a significant role in the early stages of femoral head necrosis, yet the causal relationship remains unclear. This study utilizes a two-sample Mendelian randomization (MR) approach to explore the genetic causal links between biochemical markers of bone metabolism, bone mineral density, and the risk of femoral head necrosis.MethodsThis study utilizes publicly available genome-wide association study (GWAS) datasets, with exposure factors including biochemical bone markers (25OHD, calcium, and alkaline phosphatase) and bone mineral density (measured at the lumbar spine, heel, femoral neck, and total body). The outcome of interest is osteonecrosis of the femoral head. We selected validated single nucleotide polymorphisms that are strongly associated with the exposure factors as instrumental variables. Mendelian randomization analysis was conducted using inverse variance weighting(IVW), MR-Egger regression, and weighted median estimation. Additionally, we performed analyses for horizontal pleiotropy, heterogeneity, and sensitivity.ResultsA total of 934 SNPs were included in this study. The MR analysis results indicate that the IVW analysis of 25OHD, Ca, and ALP did not reach statistical significance (25OHD OR = 1.006, 95%CI: 0.69–1.47, P = 0.975; Ca OR = 0.856, 95%CI: 0.43–1.70, P = 0.657; ALP OR = 1.022, 95%CI: 0.86–1.21, P = 0.801). However, bone density, including heel, lumbar spine, and total body bone density, showed a protective causal relationship with the onset of ONFH, while the results for femoral neck bone density did not reach statistical significance (lumbar spine BMD OR = 0.662, 95%CI: 0.48–0.91, P = 0.010; heel BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; total body BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; femoral neck BMD OR = 0.748, 95%CI: 0.53–1.05, P = 0.096). Cochran’s Q statistic for IVW and MR-Egger methods indicated no intergenic heterogeneity for all exposure outcomes’ SNPs, and the tests for pleiotropy suggested a low likelihood of pleiotropy in all causal analyses.ConclusionsThe results of this study indicate that there is no genetically mediated causal relationship between serum levels of 25-hydroxyvitamin D, calcium, and alkaline phosphatase and osteonecrosis of the femoral head. However, heel, lumbar spine, and total body bone mineral density can be considered protective factors for the occurrence of ONFH. There is no genetic causality between femoral neck bone mineral density and ONFH development.

Exploring the causal link between serum amino acids and Parkinson’s disease: a Mendelian randomization approach

This study aimed to explore the causal relationships between multiple blood amino acids (BAAs) and the Parkinson’s disease (PD). We downloaded genome-wide association study (GWAS) data for BAAs and PD from the OpenGWAS database, screened single nucleotide polymorphisms (SNPs) from the data, and evaluated the causal relationship between BAA levels and PD using the inverse variance weighted (IVW) method. The sensitivity analysis was also conducted. After SNP screening, three amino acid indicators were identified: met-a-308 (phenylalanine), met-a-584 (X-12100 hydroxytryptophan), and met-a-337 (5-hydroxyproline), which showed significant causal relationship with the occurrence of PD. There was no significant heterogeneity or horizontal pleiotropy, and the results were stable. The multivariate MR analysis showed that the mediating effects generated by the introduction of multiple variables were not significant. In conclusion, phenylalanine, X-12,100 hydroxytryptophan, and 5-hydroxyproline have a causal relationship with the occurrence of PD and may be potential early screening biomarkers and blocking targets.

The mediating effects of mobile phone use on ADHD and educational outcomes: a two-step Mendelian randomisation study.

This study investigates the potential mediating role of mobile phone screen time in the causal relationships between Attention-deficit/hyperactivity disorder (ADHD) and educational attainment. Our analysis explores both the effect of ADHD on educational outcomes and the reverse, i.e., the influence of educational attainment on ADHD risk. A two-sample Mendelian randomisation (MR) analysis was conducted using genetic instruments from genome-wide association studies (GWAS) of European populations. We employed a two-step MR approach to assess the causal effects between ADHD, mobile phone screen time (both frequency and duration), and educational outcomes, including years of full-time education and college completion. Data from public genome-wide association studies encompassing European populations with sample sizes ranging from 55,374 to 470,941 were utilised. We found significant causal associations between childhood ADHD and educational attainment, partially mediated by mobile phone screen time. Childhood ADHD was negatively linked to years of full-time education (IVW: OR = 0.93, 95% CI = 0.90-0.97, p = 0.000) and college completion (IVW: OR = 0.97, 95% CI = 0.95-0.98, p = 0.000). Mobile phone use frequency mediated 19.3% of the effect on full-time education (β = -0.158) and 11.9% on college completion (β = -0.084). The duration of phone use mediated 64.8% of the effect on college completion (β = -0.054). When ADHD was the outcome, phone use duration mediated -22.45% of full-time education effects (β = 0.426) and -19.62% of college completion (β = 0.433). Different MR models reveal the complex mediation role of mobile phone use frequency and duration between ADHD and educational attainment, varying by educational outcome type. Frequency mediates the link between childhood ADHD and full-time education/college completion, while duration significantly impacts ADHD when higher education is the outcome. The notable mediation effect of duration on ADHD underscores the need for further study into screen time's influence on ADHD and academic achievement across stages.

Chronic widespread musculoskeletal pain shares a highly heritable latent pathway with atherosclerosis and arterial stiffness

Abstract Chronic widespread pain (CWP) is prevalent and associated with reduced life expectancy. Cardiovascular disease is one possible mechanism for this. The purpose of this study was to examine the association of CWP with arterial stiffness and carotid plaque measured using ultrasound to determine if shared environmental or genetic factors might account for any observed association. Around 3000 participants from the TwinsUK with CWP information and measures of carotid–femoral pulse wave velocity (cfPWV), carotid intima–media thickness (cIMT), and plaque were considered. The relationship between CWP and cfPWV, cIMT, and plaque was determined. UK Biobank data were used to replicate the association. Cholesky decomposition and multivariate pathway twin models were examined. Using a 2-sample Mendelian randomisation approach, the causal association between CWP and coronary artery disease was assessed. TwinsUK participants demonstrated a significant association between CWP and increased cfPWV consistent with arterial stiffening (OR = 1.35, P-value = 0.012), as well as the presence of carotid plaque (OR = 1.45, P-value = 0.8e-5). The twin modelling showed a common latent component and pathway underlying CWP, cfPWV, and carotid plaque, with genetic factors accounting for 68% and 90% of the latent factor variation, respectively. The 2-sample MR revealed a potential causal association between CWP and coronary artery disease. This study found that those with CWP have increased the risk of arterial stiffness and atherosclerosis and suggests that CWP leads to an increased risk of cardiovascular disease through genetic factors.

Deciphering the causal landscape: genetic insights into sporadic vestibular schwannoma risk factors through Mendelian Randomization

BackgroundSporadic vestibular schwannoma, a benign tumor affecting the vestibulocochlear nerve, poses significant health challenges due to its impact on hearing, balance, and facial nerve function. Despite known associations with genetic mutations and environmental factors, the causality between potential risk factors and sporadic vestibular schwannoma remains underexplored.ObjectiveThis study aims to investigate the causal effects of various genetically predicted risk factors on sporadic vestibular schwannoma utilizing a Two-Sample Mendelian Randomization (MR) approach to enhance understanding of its etiology and inform prevention strategies.MethodsLeveraging data from genome-wide association studies (GWAS), we analyzed 29 risk factors across five categories: related diseases, lifestyle habits, nutritional status, learning ability, and laboratory indicators. The MR analysis employed instrumental variables (IVs) derived from single nucleotide polymorphisms (SNPs) to assess causal relationships, overcoming traditional observational study limitations.ResultsOur findings highlight significant associations between sporadic vestibular schwannoma and factors such as ovarian cancer, uterine fibroids and lifestyle habits including dietary intake and alcohol consumption. Notably, higher educational attainment and specific laboratory indicators like high-density lipoprotein (HDL) cholesterol levels were linked to altered disease risk. These results suggest a multifaceted etiology involving hormonal, cardiovascular, gastrointestinal, immune, and metabolic pathways.ConclusionThis comprehensive MR study provides novel insights into the diverse risk factors contributing to sporadic vestibular schwannoma, emphasizing the role of genetic predispositions, hormonal influences, and lifestyle choices in its development. The associations identified underscore the need for a multidisciplinary research approach and targeted public health strategies to mitigate sporadic vestibular schwannoma risk. Further research into the underlying mechanisms of these associations is crucial for developing effective interventions and improving patient outcomes.

The immune cells causative role in lung cancer: Mendelian randomization study

BackgroundsLung cancer (LC) is the leading cause of cancer-related deaths in China, with its incidence and mortality rates rising annually. Various studies have demonstrated disparities in immune cell counts and profiles between LC patients and healthy individuals. However, the existence of a causal link remains largely uncertain. To explore the potential causal association between immune cells and LC risk, a Mendelian randomization (MR) approach was employed.MethodsEmploying immune cell genome-wide association study (GWAS) data from a public database (n = 731 subjects) and Lung Cancer Genome Research Consortium's GWAS dataset (n = 492,803 participants), unconventional genetic loci remarkably associated with the significant abundance of 731 types of immune cells were extracted according to preset threshold points as instrumental variables. The primarily analytical strategy involved the inverse variance weighting (IVW) method, with the effect size estimates expressed as odds ratio (OR) and 95% CI. The robustness of the findings was assessed through a leave-one-out sensitivity analysis, heterogeneity test, horizontal gene pleiotropy test, MR-PRESSO and MR-Egger.ResultsThe MR analysis identified a significant association between 18 distinct immune cell types and lung cancer risk. MR analysis revealed that 7 types of immune cells, including CD20 on IgD − CD38 − B cell, CD20 on switched memory B cell, IgD on IgD + CD24 + B cell, BAFF − R on IgD − CD38 + B cell, CD39 + resting CD4 regulatory T cell Absolute Count, CD127 on CD45RA + CD4 + T cell, CD8 on Effector Memory CD8 + T cell, displayed a protective effect against lung cancer development. Conversely, 11 other immune cells populations were positive associated with an increased lung cancer risk. In contrast, reverse MR analysis indicated that the lung cancer risk was linked to 11 immune cells, with 2 types of immune cells (CD25 on IgD − CD27 − B cell, CD4 + T cell %leukocyte) showing a are positive correlation with cancer development, whereas 9 types of immune cells appeared to be inversely regulated. These findings collectively imply that specific immune cell populations may play critical roles in either promoting or suppressing the initiation and progression of lung cancer.ConclusionThe findings of this study offer fresh insights into the underlying biological mechanisms governing lung cancer development, thereby opening new avenues for future research in the domain of LC. The identification of specific immune cell subsets with protective or promoting roles provides crucial leads for preventive and therapeutic strategies. These insights have the potential to enhance early detection methods and inform the development of more effective treatment approaches, ultimately benefiting patient outcomes and improving the overall management of lung cancer.

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.

The mitochondrial DNA copy number and ovary-related reproductive disorders: A bidirectional two-sample Mendelian randomization study.

In the present study, a bidirectional two-sample Mendelian randomization approach was utilized to explore potential causal relationships between mitochondrial DNA copy number (mtDNA-CN) and ovary-related reproductive disorders (ORRDs), including ovarian dysfunction, ovarian cyst, polycystic ovary syndrome (PCOS), premature ovarian failure (POF) and ovarian endometriosis. Genetic associations with mtDNA-CN were obtained from three genome-wide association study (GWAS) summary statistics from the UK Biobank, and ORRD data were investigated using summary statistics from the FinnGen cohort. Single nucleotide polymorphisms (SNPs) correlated with mtDNA-CN were selected as genetic instrumental variables (IVs) to estimate the causal effect of mtDNA-CN on ORRDs using the inverse-variance weighted (IVW) method with heterogeneity and pleiotropy analysis, and we repeated this in the opposite direction using instruments for ORRDs. We found that the genetically predicted mtDNA was indicative of increased levels of PCOS (OR = 1.16; P < 0.001) and ovarian endometriosis (OR = 1.25; P = 0.007) in the IVW analysis and was not associated with the risk of other ORRDs. In the reverse direction, genetically predicted ORRDs were not associated with mtDNA-CN levels in the IVW analysis. Sensitivity and replication analyses showed the results to be stable. We found that mtDNA-CN may increase the risk of PCOS and ovarian endometriosis. This may have implications for mtDNA-CN as a biomarker for these conditions in clinical practice.

Using a two sample Mendelian randomization approach to explore the causal relationship between erectile dysfunction and lung function.

Recently, some observational studies have suggested potential associations between erectile dysfunction (ED) and respiratory function. However, the underlying biological mechanisms and causal relationships between ED and lung function require further investigation. This study aimed to explore the causalities between ED and lung function traits. Single-nucleotide polymorphisms (SNPs) for ED were extracted from the Finngen_r7 (1,154 cases and 94,024 controls), and the summary statistics of respiratory function were extracted from the UK Biobank (UKB) (n=321,047). We utilized several Mendelian randomization (MR) methods to mitigate the impact of weak instrument bias and pleiotropy. To address potential confounding effects, multivariable MR (MVMR) analyses were also conducted, adjusting for demographic factors and respiratory conditions. Moreover, recently developed latent causal variable (LCV) modeling was also performed to enhance the robustness of the findings. Totally 15 SNPs robustly associated with ED were included. We found that higher risk of ED was associated with decreased of forced expiratory volume in the first second (FEV1) [odds ratio (OR) 0.992, 95% confidence interval (CI): 0.986, 0.997, P=0.003], as was the case for forced vital capacity (FVC) (OR 0.994, 95% CI: 0.989, 1.000, P=0.04), peak expiratory flow (PEF) (OR 0.990, 95% CI: 0.990, 0.990, P=0.01) and FEV1/FVC ratio (OR 0.991, 95% CI: 0.985, 0.997, P=0.002). After adjusting for confounding factors, ED only demonstrated causal effects on FEV1/FVC ratio. Notably, the LCV analysis provided additional support for the positive causal impact of ED on FEV1 and FVC. Conversely, reverse MR analysis did not reveal compelling evidence for a causal effect of lung function on ED. Our study suggests a potential causal relationship between higher ED susceptibility and reduced respiratory function, as indicated by decreased FEV1, FVC, PEF, and the FEV1/FVC ratio. The results enhanced understanding of the intricate interrelationships between ED and lung function.

Unraveling the hidden link: neuroticism as a risk factor for upper urinary tract calculi-insights from Mendelian randomization analysis.

Upper urinary tract calculi (UUTC) are major risk factors for renal insufficiency and nephrectomy with psychological distress, notably depression and anxiety, being common among affected patients. Depression and anxiety are associated with heightened neuroticism. Individuals with neuroticism frequently exhibit a range of urological disorders. Given the limited research on UUTC and neuroticism, this study aims to explore this relationship using Mendelian randomization (MR) analysis. We assessed the effects of neuroticism and associated psychological traits on UUTC using a two-sample MR approach, primarily employing the inverse variance weighted (IVW) method, with additional analysis via MR-Egger and weighted median methods. To ensure robustness, we conducted sensitivity analyses using Cochran's Q test, MR-Egger intercept, and MR-pleiotropy residual sum and outlier (PRESSO). At the same time, we selected the neuroticism score for verification queue of the exposure. Furthermore, to explore the independent effects of neuroticism traits on UUTC, we performed multivariable MR analyses on phenotypes with no pleiotropy, IVW P values below 0.05, and consistent directions across all three MR methods. Our MR analysis revealed a significant causal impact of neuroticism on UUTC using the IVW [odds ratio (OR) =1.15, 95% confidence interval (CI): 1.02 to 1.29, P=0.03) and weighted median (OR =1.22, 95% CI: 1.03 to 1.44, P=0.02) methods. Verification queue similarly confirmed that the neuroticism score was a risk factor for UUTC (IVW, OR =1.11, 95% CI: 1.03 to 1.19, P=0.007). Sensitivity analyses indicated no heterogeneity or pleiotropy. Additionally, IVW analyses identified experiencing mood swings (OR =1.41, P=0.047), feeling lonely (OR =6.03, P<0.001), and feeling worry (OR =1.58, P=0.03) as significantly associated with UUTC. Multivariate MR analysis showed that experiencing mood swings is a stand-alone risk factor for UUTC (OR =1.75, P=0.03). Our MR analysis has pinpointed neuroticism as a risk factor for UUTC, with experiencing mood swings identified as an independent risk factor for UUTC, offering new insights into the brain-kidney connection. The exact pathways driving this relationship require further study. These results highlight the necessity of vigilant urinary stone surveillance in individuals exhibiting neurotic traits.

Hemoglobin levels in red blood cells and risk of colorectal cancer: A causal investigation based on Mendelian randomization.

Mean corpuscular hemoglobin (MCH) is a critical parameter in red blood cells, associated with various diseases. While studies suggest a potential link between MCH levels and colorectal cancer (CRC), observational studies are insufficient to establish causality directly. This study utilized a 2-sample Mendelian randomization (MR) approach to investigate the genetic causal relationship between MCH and colorectal cancer (CRC). Genome-wide association study (GWAS) summary data for both MCH and CRC were sourced from relevant databases. MR analyses were performed using methods including inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode. Cochrane's Q test was applied to assess heterogeneity in the MR findings. Horizontal pleiotropy was evaluated using the MR-Egger intercept test and the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Additionally, a leave-one-out analysis was conducted to assess the robustness of this association. The IVW method demonstrated that MCH is an independent risk factor for colorectal cancer (P = .013). Horizontal pleiotropy is unlikely to influence the causal relationship (P > .05), and there was no evidence of heterogeneity among the genetic variants (P > .05). Lastly, the leave-one-out test confirmed the stability and robustness of the association. All participants in the GWAS were derived from a specific population. Due to limitations inherent to the database, the Mendelian Randomization (MR) analysis was unable to incorporate stratified analyses by country, ethnicity, or age group.

Impact of breakfast skipping on esophageal health: A mendelian randomization study

Background & AimsPrevious studies have indicated that, in addition to the types of food consumed, eating habits are also associated with the risk of esophageal diseases. Some studies have suggested a possible link between breakfast skipping and esophageal tumors as well as gastroesophageal reflux disease. However, it remains unclear whether breakfast skipping has a causal relationship with esophageal diseases. To address this issue, this study aimed to investigate the potential causal relationship between breakfast skipping and esophageal diseases using a two-sample mendelian randomization (MR) approach. MethodsWe obtained data from genome-wide association studies (GWAS) involving 193,860 individuals from the UK Biobank on breakfast skipping. The summary statistics for the esophageal diseases were derived from the IEU open GWAS project. In this two-sample MR analysis, inverse variance weighted was used, supplemented with weighted median, simple mode and weighted mode methods. ResultsThe results revealed significant causal relationships between breakfast skipping and esophageal cancer (odds ratio (OR): 5.992, 95% confidence interval (CI): 1.606-22.350, p=0.008), Barrett’s esophagus (OR: 4.041, 95% CI: 1.837-8.889, p<0.001), gastroesophageal reflux disease (OR: 2.463, 95% CI: 1.995-3.041, p<0.001), and esophageal varices (OR: 4.454, 95% CI: 1.785-11.112, p=0.001). All of the supplementary methods supported the findings. ConclusionOur research provides evidence for the association between breakfast skipping and esophageal diseases. Breakfast skipping could be a potential risk factor for esophageal cancer, Barrett's esophagus, gastroesophageal reflux disease and esophageal varices. For high-risk groups prone to these esophageal diseases, emphasizing the importance of regular breakfast and maintaining consistent dietary habits is crucial for esophageal health.

The Relationship Between PM2.5 and Eight Common Lung Diseases: A Two-Sample Mendelian Randomization Analysis

Air pollutants have both acute and chronic impacts on human health, affecting multiple systems and organs. While PM2.5 exposure is commonly assumed to be strongly associated with all respiratory diseases, this relationship has not been systematically analyzed. This study employed a two-sample Mendelian randomization approach to investigate the effects of PM2.5 on eight common lung diseases, using data from GWAS. Additionally, multivariable Mendelian randomization was applied to assess the direct effects of various air pollutants and the mediating roles of common factors such as BMI and smoking. At a significance threshold of 5×10−8, PM2.5 showed a significant causal relationship with both asthma and COPD. When the screening threshold was relaxed to 5× 10−6, this exposure continued to demonstrate significant associations not only with asthma and COPD, but also with other respiratory diseases, including pneumonia, emphysema/chronic bronchitis, and lung cancer. In the multivariable Mendelian randomization analysis, which controlled for smoking and bacterial infections, the association with pneumonia became non-significant, while the relationships with the other four diseases persisted. This study provides a systematic exploration of the relationship between PM2.5 and eight pulmonary diseases from a new perspective, deepening our understanding of the impact of air pollution on health and laying the foundation for future efforts to mitigate these effects.