Mendelian randomization supports causal effects of inflammatory biomarkers on myopic refractive errors.

AIMS: To determine whether inflammatory biomarkers are causal risk factors for more myopic refractive errors. METHODS: Northern Sweden Population Health Study (NSPHS), providing inflammatory biomarkers data; UK Biobank, providing refractive errors data. 95,619 European men and women aged 40 to 69 years with available information of refractive errors and inflammatory biomakers. Inflammatory biomarkers including ADA, CCL23, CCL25, CD6, CD40, CDCP-1, CST5, CXCL-5, CXCL-6, CXCL-10, IL-10RB, IL-12B, IL-15RA, IL-18R1, MCP-2, MMP-1, TGF-ß1, TNF-ß, TWEAK and VEGF-A were exposures, and spherical equivalent (SE) using the formula SE = sphere + (cylinder/2) was outcome. RESULTS: Mendelian randomization analyses showed that each unit increase in VEGF-A, CD6, MCP-2 were causally related to a more myopic refractive errors of 0.040 D/pg.mL-1 (95% confidence interval 0.019 to 0.062; P = 2.031 × 10-4), 0.042 D/pg.mL-1 (0.027 to 0.057; P = 7.361 × 10-8) and 0.016 D/pg.mL-1 (0.004 to 0.028; P = 0.009), and each unit increase in TWEAK was causally related to a less myopic refractive errors of 0.104 D/pg.mL-1 (-0.152 to -0.055; P = 2.878 × 10-5). Tested by the MR-Egger, weighted median, MR-PRESSO, Leave-one-out methods, our results were robust to horizontal pleiotropy and heterogeneity in VEGF-A, MCP-2, CD6, but not in TWEAK. CONCLUSIONS: Our Mendelian Randomization analysis supported the causal effects of VEGF-A, MCP-2, CD6 and TWEAK on myopic refractive errors. These findings are important for providing new indicators for early intervention of myopia to make myopic eyesight threatening consequences less inevitable.

Revealing an association between HPV and systemic lupus erythematosus: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: An increasing number of studies have focused on the association between Human papillomavirus (HPV) infection and systemic lupus erythematosus (SLE). However, current evidence is largely based on retrospective studies, which are susceptible to confounding factors and cannot establish causation. METHODS: A bidirectional two-sample Mendelian randomization (MR) design was used to evaluate the causal relationship between HPV and SLE. Mononucleoside polymers (SNPS) with strong evidence for genome-wide association studies (GWAS) were selected from the HPV exposure dataset and used as an instrumental variable (IV) for this study. For the MR Analysis results, the MR-Egger intercept P test, MR-Presso global test, CochranQ test and leave-one test were used for sensitivity analysis. RESULTS: Based on the evidence of MR Analysis, this study finally determined that there was no causal association between HPV16 and HPV18 and SLE. CONCLUSIONS: Possible regulation of HPV infection is not significantly associated with regulation of SLE. These findings provide new insights into the underlying mechanisms of HPV and SLE and need to be validated by further studies.

Causal relationship between body mass index and anal fistula: a two-sample Mendelian randomization study.

Background: Significant evidence has been documented regarding the intricate connection between the development of anal fistula (AF) and the composition of Body Mass Index (BMI). Nevertheless, due to the inherent limitations of reverse causality and confounders inherent in observational studies, this relationship remains unclarified. Our study aims to reveal the causal impact between BMI and AF, as well as identify its associated risk factors, thereby providing a more comprehensive understanding of this complex interaction. Methods: Single nucleotide polymorphisms (SNPs) identified through genome-wide association study (GWAS) databases were used as instrumental variables for analysis. BMI served as the exposure variable, with six pooled GWAS datasets included. AF was the outcome variable. The Inverse Variance Weighted (IVW) method was used as the primary analytical technique, with MR-Egger regression, Weighted Median (WME) estimation, and Multiplicity Residual Sum and Outlier (MR-PRESSO) tests serving as secondary validations of the IVW results. Odds ratios (OR) were utilized as indicators to evaluate the causal relationship between BMI and AF. Results: A total of 738 SNPs strongly associated with the exposure were identified as instrumental variables. The IVW results demonstrated a positive correlation between BMI and the risk of AF. The MR-Egger analysis yielded p-values greater than 0.05, indicating no pleiotropic effects among the selected SNPs. Cochran's Q test also resulted in p-values greater than 0.05, suggesting no significant heterogeneity among the instrumental variables. The MR-PRESSO analysis revealed no horizontal pleiotropy or outliers potentially violating the causal assumption (p > 0.05). Conclusion: High BMI is positively associated with the risk of AF, and correcting BMI levels may have a preventive effect on the incidence of AF.

The causal relationship between 91 inflammatory cytokines and Gestational Diabetes Mmellitus: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Gestational Diabetes Mellitus (GDM) poses significant risks to maternal and fetal health, yet its precise etiology remains unclear. Observational studies have demonstrated a link between specific inflammatory cytokines and the occurrence of GDM, but the causal relationships remain uncertain. METHODS: Utilizing publicly accessible genetic data, we performed a bidirectional two-sample mendelian randomization (MR) analysis to elucidate the causal association between 91 inflammatory cytokines and GDM. Sensitivity analysis was carried out to evaluate the robustness, heterogeneity, and potential presence of horizontal pleiotropy within the results. RESULTS: Elevated levels of Interleukin-7 (IL7) and Neurturin (NRTN) (OR=1.104, 95 % CI=1.003-1.216, p = 0.042; OR=1.102, 95 % CI=1.023-1.187, p = 0.010), along with decreased levels of Glial cell line-derived neurotrophic factor (GDNF), Interleukin-12 subunit beta (IL12ß), and Interleukin-20 (IL20) (OR=0.911, 95 % CI=0.849-0.979, p = 0.010;OR=0.955, 95 % CI=0.916-0.996, p = 0.033; OR=0.892, 95 % CI=0.819-0.971, p = 0.008), are associated with increased GDM risk. Additionally, GDM occurrence correlates with increased Matrix metalloproteinase-10 (MMP-10) and decreased Interleukin-20 receptor subunit alpha (IL-20Rα) levels (OR=1.042, 95 % CI=1.002-1.084, p = 0.038; OR=0.949, 95 % CI=0.909-0.992, p = 0.021). Sensitivity analyses detected no significant heterogeneity or pleiotropy. CONCLUSION: This study has clarified the causal link between inflammatory cytokines and GDM, thereby enhancing our comprehension of the potential mechanisms involved in GDM pathogenesis. These findings offer new insights into the etiology, diagnosis, and therapeutic strategies for GDM.

Rheumatoid arthritis and adverse pregnancy outcomes: a bidirectional two-sample mendelian randomization study.

BACKGROUND: There is growing evidence of bidirectional associations between rheumatoid arthritis and adverse pregnancy outcomes (APOs) in observational studies, but little is known about the causal direction of these associations. Therefore, we explored the potential causal relationships between rheumatoid arthritis and APOs using a bidirectional two-sample Mendelian randomization (MR) in European and Asian populations. METHODS: We conducted a bidirectional two-sample Mendelian randomization analysis using available summary statistics from released genome-wide association studies. Summary statistics for instrument-outcome associations were retrieved from two separate databases for rheumatoid arthritis and adverse pregnancy outcomes, respectively. The inverse-variance weighted method was used as the primary MR analysis, and cML-MA-BIC was used as the supplementary analysis. MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran Q statistic method were implemented as sensitivity analyses approach to ensure the robustness of the results. RESULTS: Our study showed that a higher risk of rheumatoid arthritis in the European population was associated with gestational hypertension (OR: 1.04, 95%CI: 1.02-1.06), pre-eclampsia (OR: 1.06, 95%CI: 1.01-1.11), fetal growth restriction (OR: 1.08, 95%CI: 1.04-1.12), preterm delivery (OR:1.04, 95%CI: 1.01-1.07). Furthermore, we found no evidence that APOs had causal effects on rheumatoid arthritis in the reverse MR analysis. No association between rheumatoid arthritis and APOs was found in East Asian population. There was no heterogeneity or horizontal pleiotropy. CONCLUSIONS: This MR analysis provides the positive causal association from rheumatoid arthritis to gestational hypertension, pre-eclampsia, fetal growth restriction and preterm delivery genetically. It highlights the importance of more intensive prenatal care and early intervention among pregnant women with rheumatoid arthritis to prevent potential adverse obstetric outcomes.

Exploring the Causal Relationship Between Migraine and Insomnia Through Bidirectional Two-Sample Mendelian Randomization: A Bidirectional Causal Relationship.

Introduction: The intricate relationship between migraine and insomnia has been a subject of great interest due to its complex mechanisms. Despite extensive research, understanding the causal link between these conditions remains a challenge. Material and Methods: This study employs a bidirectional Mendelian randomization approach to investigate the causal relationship between migraine and insomnia. Risk loci for both conditions were derived from large-scale Genome-Wide Association Studies (GWAS). The primary method of Mendelian Randomization utilized in this study is the Inverse Variance Weighted (IVW) method. Results: Our findings indicate a bidirectional causal relationship between migraine and insomnia. In the discovery set, migraine had a significant effect on insomnia (OR=1.02, 95% CI=1.02 (1.01-1.03), PIVW=5.30E-04). However, this effect was not confirmed in the validation set (OR=1.03, 95% CI=1.03 (0.87-1.21), PIVW=0.77). Insomnia also had a significant effect on migraine (OR=1.02, 95% CI=1.02 (0.01-1.03), PIVW=2.67E-08), and this effect was validated in the validation set (OR=2.30, 95% CI=2.30 (1.60-3.30), PIVW=5.78E-06). Conclusion: This study provides meaningful insights into the bidirectional causality between migraine and insomnia, highlighting a complex interplay between these conditions. While our findings advance the understanding of the relationship between migraine and insomnia, they also open up new avenues for further research. The results underscore the need for considering both conditions in clinical and therapeutic strategies.

Mendelian randomization study of inflammatory bowel disease and type 1 diabetes.

PURPOSE: Our purpose was to investigate and test the causal relationship between type 1 diabetes (T1D) and inflammatory bowel disease (IBD) and its major phenotypes, including ulcerative colitis (UC) and Crohn's disease (CD), in two large datasets. METHODS: We obtained IBD samples from the largest publicly available genome-wide association study (GWAS), as well as the FinnGen database and the publicly accessible IEU GWAS database of T1D. We employed a two-sample Mendelian randomization approach to assess bidirectional causality using the inverse variance weighting (IVW) method as the primary outcome. RESULTS: Genetic predisposition to T1D was associated with reduced risk of IBD (IVW: odds ratio (OR), 0.867; 95% confidence interval (CI), [0.852, 0.883]; P < 0.001), UC (OR = 0.879 [0.823, 0.939], P < 0.001), and CD (OR = 0.925 [0.872, 0.981], P = 0.009). The republication results found IBD genetically possessed negative association with T1D (OR = 0.781 [0.684, 0.891], P < 0.001). Additionally, a meta-analysis of results was conducted to prove the strong evidence between T1D and CD (OR = 0.95 [0.91, 0.98]; p = 0.01). CONCLUSIONS: This study first demonstrated a causal effect of TID on the reduced risk of CD in the mendelian randomization study.

The causal relationship between human brain morphometry and knee osteoarthritis: a two-sample Mendelian randomization study.

Background: Knee Osteoarthritis (KOA) is a prevalent and debilitating condition affecting millions worldwide, yet its underlying etiology remains poorly understood. Recent advances in neuroimaging and genetic methodologies offer new avenues to explore the potential neuropsychological contributions to KOA. This study aims to investigate the causal relationships between brain-wide morphometric variations and KOA using a genetic epidemiology approach. Method: Leveraging data from 36,778 UK Biobank participants for human brain morphometry and 487,411 UK Biobank participants for KOA, this research employed a two-sample Mendelian Randomization (TSMR) approach to explore the causal effects of 83 brain-wide volumes on KOA. The primary method of analysis was the Inverse Variance Weighted (IVW) and Wald Ratio (WR) method, complemented by MR Egger and IVW methods for heterogeneity and pleiotropy assessments. A significance threshold of p < 0.05 was set to determine causality. The analysis results were assessed for heterogeneity using the MR Egger and IVW methods. Brain-wide volumes with Q_pval < 0.05 were considered indicative of heterogeneity. The MR Egger method was employed to evaluate the pleiotropy of the analysis results, with brain-wide volumes having a p-value < 0.05 considered suggestive of pleiotropy. Results: Our findings revealed significant causal associations between KOA and eight brain-wide volumes: Left parahippocampal volume, Right posterior cingulate volume, Left transverse temporal volume, Left caudal anterior cingulate volume, Right paracentral volume, Left paracentral volume, Right lateral orbitofrontal volume, and Left superior temporal volume. These associations remained robust after tests for heterogeneity and pleiotropy, underscoring their potential role in the pathogenesis of KOA. Conclusion: This study provides novel evidence of the causal relationships between specific brain morphometries and KOA, suggesting that neuroanatomical variations might contribute to the risk and development of KOA. These findings pave the way for further research into the neurobiological mechanisms underlying KOA and may eventually lead to the development of new intervention strategies targeting these neuropsychological pathways.

Endometriosis is a disease of immune dysfunction, which could be linked to microbiota.

Background: Endometriosis, characterized by extrauterine endometrial tissue, leads to irregular bleeding and pelvic pain. Menstrual retrograde theory suggests fragments traverse fallopian tubes, causing inflammation and scar tissue. Prevalent among infertile women, risk factors include fewer pregnancies, delayed childbirth, irregular cycles, and familial predisposition. Treatments, medication, and surgery entail side effects. Studies link gut microbiota alterations to endometriosis, necessitating research to establish causation. We used Mendelian randomization to investigate the potential link between endometriosis and gut microbiota through genetic variants. Methods: Two-sample Mendelian randomization analyzed gut microbiota's potential causal effects on endometriosis. Instrumental variables, robustly associated with exposures, leveraged GWAS data from MiBioGen for gut microbiota and FinnGen R8 release for endometriosis. SNPs strongly associated with exposures were instrumental variables. Rigorous assessments ensured SNP impact scrutiny on endometriosis. Results: At the genus level, Anaerotruncus, Desulfovibrio, Haemophilus, and Holdemania showed causal association with endometriosis. Specific gut microbiota exhibited causal effects on different endometriosis stages. Holdemania and Ruminococcaceae UCG002 exerted reversible, stage-specific impacts. Conclusion: Mendelian randomization provides evidence for the causal link between specific gut microbiotas and endometriosis, emphasizing the pivotal role of gut microbiota dysbiosis. Modulating gut microbiota emerges as a promising strategy for preventing and treating endometriosis.

Bidirectional two-sample Mendelian randomization study of association between smoking initiation and atrial fibrillation.

INTRODUCTION: The relationship between smoking and heart disease has been frequently reported. Therefore, we aimed to explore the association between smoking initiation and atrial fibrillation. METHODS: Genetic association data pertaining to smoking initiation and atrial fibrillation were obtained from genome-wide association studies (GWAS). Phenotypically related single nucleotide polymorphisms (SNPs) were selected as instrumental variables. Inverse-variance weighted (IVW), weighted median, Mendelian randomization (MR), Egger regression, simple mode, and weighted mode methods were employed to perform the MR study. The association between smoking initiation and atrial fibrillation was evaluated using odds ratios (OR) and 95% confidence intervals (CI). Cochran's Q test was employed to assess heterogeneity among instrumental variables, utilizing the IVW and MR-Egger methods. The Egger-intercept method was employed to test for horizontal pleiotropy, and the 'leave-one-out' method was utilized for sensitivity analysis. RESULTS: The MR results for the effect of smoking initiation on atrial fibrillation (IVW, OR=1.11; 95% CI: 1.02-1.20, p=0.013) supported an association between smoking initiation and an increased likelihood of atrial fibrillation. In total, 85 SNPs were extracted from the GWAS pooled data as instrumental variables. The MR-Egger method indicated an intercept close to 0 (Egger intercept= -0.005, p=0.371), suggesting no horizontal pleiotropy in the selected instrumental variables. The 'leave-one-out' sensitivity analysis demonstrated that the results were robust and that no instrumental variables significantly influenced the results. Reverse MR analysis indicated no effect of atrial fibrillation on smoking initiation (IVW, OR=1.00; 95% CI: 0.99-1.02, p=0.684). CONCLUSIONS: Smoking initiation has a significant impact on atrial fibrillation. However, atrial fibrillation did not influence smoking initiation. This study provides novel insights into the genetic relationships between smoking initiation and atrial fibrillation.

Causal relationship between depression and metabolic dysfunction-associated steatotic liver disease: a bidirectional Mendelian randomized study.

Background: With the global rise in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease. Concurrently, depression is a highly prevalent mental disorder. As the incidence of MASLD and depression continues to increase, a growing body of research indicates a potential association between the two conditions. However, the direction of causality between depression and MASLD remains uncertain. To address this gap, our study utilizes a two-sample Mendelian randomization (MR) approach to explore the bidirectional causal relationship between depression and MASLD. Methods: We extracted single nucleotide polymorphisms (SNPs) associated with depression and MASLD from pooled data of genome-wide association studies (GWAS). A comprehensive assessment of possible causality was also performed. Possible mediating effects of liver enzymes on MASLD were also assessed. Results: A total of three GWAS pooled data on depression as well as GWAS data related to MASLD and GWAS data on four liver enzymes were used in this study. Our findings indicated a strong causal relationship between depression and MASLD (OR, 1.557; 95% CI, 1.097-2.211; P = 0.016). And we found a mediating effect of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT 10% (95% CI: 7% - 13%, P< 0.0002). AST, 4.14% (95% CI: 2.34% - 5.94%, P < 0.05). GGT 0.19% (95% CI: 0.15% - 0.22%, P< 0.000000002). However, we did not find a mediating effect of alkaline phosphatase (ALP). Our inverse MR analysis did not reveal any causal relationship between MASLD and depression. Conclusions: The MR analysis revealed a positive causal relationship between depression and MASLD, while no reverse causal relationship was identified. Liver enzymes may mediate the role between depression and MASLD.

Investigating the causal relationship between thyroid dysfunction diseases and osteoporosis: a two-sample Mendelian randomization analysis.

The prevalence of thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) is high. Previous studies have indicated a potential association between TDFDs and OP, yet the causal direction remains unclear. This study aimed to investigate the potential causal relationship between TDFDs and the risk of developing OP and related fractures. We obtained pooled data from genome-wide association studies (GWASs) conducted on TDFDs and OP in European populations and identified single-nucleotide polymorphisms (SNPs) with genome-wide significance levels associated with exposure to TDFDs as instrumental variables. Inverse variance weighted (IVW) was employed as the primary method for Mendelian randomization (MR) analysis, supplemented by MR‒Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were conducted to evaluate the robustness of the findings. The IVW method demonstrated an increased risk of OP in patients with TDFDs, including hyperthyroidism and hypothyroidism (TDFDs: OR = 1.11; 95% CI 1.09, 1.13; hypothyroidism: OR = 1.14; 95% CI 1.10, 1.17; hyperthyroidism: OR = 1.09; 95% CI 1.06, 1.12). These findings were supported by supplementary analysis, which revealed a positive correlation between TDFDs and the risk of OP. Multiple sensitivity analyses confirmed the absence of horizontal pleiotropy in the study, thus indicating the robustness of our results. The causal relationship between TDFDs and increased risk of OP implies the need for early bone mineral density (BMD) screening and proactive prevention and treatment strategies for individuals with TDFDs.

Osteoporosis and coronary heart disease: a bi-directional Mendelian randomization study.

Background: Osteoporosis (OP) and cardiovascular disease (CVD) are major global public health issues, especially exacerbated by the challenges of an aging population. As these problems intensify, the associated burden on global health is expected to increase significantly. Despite extensive epidemiological investigations into the potential association between OP and CVD, establishing a clear causal relationship remains elusive. Methods: Instrumental variables were selected from summary statistics of the IEU GWAS database. Five different components of BMD (heel BMD, LS BMD, FA BMD, FN BMD, and TB BMD) were used as OP phenotypes. CHD, MI, and stroke were selected to represent CVD. Multiple analysis methods were used to evaluate the causal relationship between CVD and OP comprehensively. In addition, sensitivity analyses(Cochran's Q test, MR-Egger intercept test, and "leave one out" analysis) were performed to verify the reliability of the results. Results: The MR showed a significant causal relationship between CHD on heel BMD and TB BMD; in the reverse analysis, there was no evidence that OP has a significant causal effect on CVD. The reliability of the results was confirmed through sensitivity analysis. Conclusion: The study results revealed that CHD was causally associated with Heel BMD and TB BMD, while in the reverse MR analysis, the causal relationship between OP and CVD was not supported. This result posits CHD as a potential etiological factor for OP and prompts that routine bone density assessment at traditional sites (forearm, femoral neck, lumbar spine) using DAX may inadequately discern underlying osteoporosis issues in CHD patients. The recommendation is to synergistically incorporate heel ultrasound or DAX for total body bone density examinations, ensuring clinical diagnostics are both precise and reliable. Moreover, these findings provide valuable insights for public health, contributing to the development of pertinent prevention and treatment strategies.

The association between telomere length and blood lipids: a bidirectional two-sample Mendelian randomization study.

Background: Observational studies suggest an association between telomere length (TL) and blood lipid (BL) levels. Nevertheless, the causal connections between these two traits remain unclear. We aimed to elucidate whether genetically predicted TL is associated with BL levels via Mendelian randomization (MR) and vice versa. Methods: We obtained genetic instruments associated with TL, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (ApoA-1) and apolipoprotein B (ApoB) from large-scale genome-wide association studies (GWASs). The causal relationships between TL and BL were investigated via bidirectional MR, multivariable MR and mediation analysis methods. The inverse variance weighted (IVW) method was employed as the principal methodology, complemented by several other estimators to enhance the robustness of the analysis. Results: In the forward MR analyses, we identified significant positive correlation between genetically predicted TL and the levels of TG (ß=0.04, 95% confidence interval [CI]: 0.01 to 0.06, p = 0.003). In the reverse MR analysis, TG (ß=0.02, 95% CI: 0.01 to 0.03, p = 0.004), LDL-C (ß=0.03, 95% CI: 0.01 to 0.04, p = 0.001) and ApoB (ß=0.03, 95% CI: 0.01 to 0.04, p = 9.71×10-5) were significantly positively associated with TL, although this relationship was not observed in the multivariate MR analysis. The mediation analysis via two-step MR showed no significant mediation effects acting through obesity-related phenotypes in analysis of TL with TG, while the effect of LDL-C on TL was partially mediated by body mass index (BMI) in the reverse direction, with mediated proportion of 12.83% (95% CI: 0.62% to 25.04%). Conclusions: Our study indicated that longer TL were associated with higher TG levels, while conversely, higher TG, LDL-C, and ApoB levels predicted longer TL, with BMI partially mediating these effects. Our findings present valuable insights into the development of preventive strategies and interventions that specifically target TL-related aging and age-related diseases.

Causal role of immune cells in hypertension: a bidirectional Mendelian randomization study.

Background: Although Hypertension (HTN) is considered to be a cardiovascular disease caused by multiple factors, the cause of it is still unknown. In this study, we aim to find out whether circulating immune cell characteristics have an impact on susceptibility to HTN. Methods: This study employed a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the causal association between immune cell characteristics and HTN. Utilizing publicly accessible genetic data, we examined the causal relationship between HTN and the susceptibility to 731 immune cell signatures. To ensure the reliability and validity of the findings, a comprehensive sensitivity analysis was conducted to assess heterogeneity, confirm the robustness of the results and evaluate the presence of horizontal pleiotropy. Results: After FDR correction, immune phenotype had an effect on HTN. In our study, one immunophenotype was identified as being positively associated with HTN risk significance: HLA DR on CD33- HLA DR+. In addition, we examined 8 immune phenotype with no statistically significant effect of HTN, but it is worth mentioning that they had an unadjusted low P-value phenotype. Conclusions: Our MR study by genetic means demonstrated the close relationship between HTN and immune cells, thus providing guidance for future clinical prediction and subsequent treatment of HTN.

Causal role of immune cells on cervical cancer onset revealed by two-sample Mendelian randomization study.

Cervical cancer (CC) is a prevalent gynecological cancer worldwide that significantly impacts the quality of life and the physical and mental well-being of women. However, there have been limited studies utilizing Mendelian randomization (MR) analysis to investigate the connection between immune cells and CC. This study is to investigate the causal effects of immune traits on CC and non-neoplastic conditions of the cervix. The GWAS data for 731 immunophenotypes and six GWAS data for CC from the FinnGen database were downloaded. Subsequently, a two-sample MR analysis was conducted using the MR Egger, Weighted median, Inverse variance weighted (IVW), Simple mode, and Weighted mode methods. Our study has identified the potential causal effects of immune traits on inflammatory diseases of the cervix, other noninflammatory disorders of the cervix uteri, carcinoma in situ of cervix uteri, adenocarcinomas of cervix, squamous cell neoplasms and carcinoma of cervix, as well as malignant neoplasm of the cervix uteri, with the respective numbers being 8, 6, 11, 8, 23, and 12, respectively. A strong correlation between classic monocytes and various cervical diseases was revealed. Furthermore, we discovered that B cells expressing BAFF-R have the ability to impede the advancement of malignant CC, specifically squamous cell neoplasms and carcinoma of cervix. Our study has demonstrated a significant association between immune traits and both CC and non-neoplastic conditions of the cervix through two-sample Mendelian randomization, providing valuable insights for future clinical research.

Causal relationship between resting-state networks and depression: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Cerebral resting-state networks were suggested to be strongly associated with depressive disorders. However, the causal relationship between cerebral networks and depressive disorders remains controversial. In this study, we aimed to investigate the effect of resting-state networks on depressive disorders using a bidirectional Mendelian randomization (MR) design. METHODS: Updated summary-level genome-wide association study (GWAS) data correlated with resting-state networks were obtained from a meta-analysis of European-descent GWAS from the Complex Trait Genetics Lab. Depression-related GWAS data were obtained from the FinnGen study involving participants with European ancestry. Resting-state functional magnetic resonance imaging and multiband diffusion imaging of the brain were performed to measure functional and structural connectivity in seven well-known networks. Inverse-variance weighting was used as the primary estimate, whereas the MR-Pleiotropy RESidual Sum and Outliers (PRESSO), MR-Egger, and weighted median were used to detect heterogeneity, sensitivity, and pleiotropy. RESULTS: In total, 20,928 functional and 20,573 structural connectivity data as well as depression-related GWAS data from 48,847 patients and 225,483 controls were analyzed. Evidence for a causal effect of the structural limbic network on depressive disorders was found in the inverse variance-weighted limbic network (odds ratio, [Formula: see text]; 95% confidence interval, [Formula: see text]; [Formula: see text]), whereas the causal effect of depressive disorders on SC LN was not found(OR=1.0025; CI,1.0005-1.0046; P=0.012). No significant associations between functional connectivity of the resting-state networks and depressive disorders were found in this MR study. CONCLUSIONS: These results suggest that genetically determined structural connectivity of the limbic network has a causal effect on depressive disorders and may play a critical role in its neuropathology.

Association between gut microbiota and spinal stenosis: a two-sample mendelian randomization study.

Introduction: Considerable evidence has unveiled a potential correlation between gut microbiota and spinal degenerative diseases. However, only limited studies have reported the direct association between gut microbiota and spinal stenosis. Hence, in this study, we aimed to clarify this relationship using a two-sample mendelian randomization (MR) approach. Materials and Methods: Data for two-sample MR studies was collected and summarized from genome-wide association studies (GWAS) of gut microbiota (MiBioGen, n = 13, 266) and spinal stenosis (FinnGen Biobank, 9, 169 cases and 164, 682 controls). The inverse variance-weighted meta-analysis (IVW), complemented with weighted median, MR-Egger, weighted mode, and simple mode, was used to elucidate the causality between gut microbiota and spinal stenosis. In addition, we employed mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and the MR-Egger intercept test to assess horizontal multiplicity. Cochran's Q test to evaluate heterogeneity, and "leave-one-out" sensitivity analysis to determine the reliability of causality. Finally, an inverse MR analysis was performed to assess the reverse causality. Results: The IVW results indicated that two gut microbial taxa, the genus Eubacterium fissicatena group and the genus Oxalobacter, have a potential causal relationship with spinal stenosis. Moreover, eight potential associations between genetic liability of the gut microbiota and spinal stenosis were implied. No significant heterogeneity of instrumental variables or horizontal pleiotropy were detected. In addition, "leave-one-out" sensitivity analysis confirmed the reliability of causality. Finally, the reverse MR analysis revealed that no proof to substantiate the discernible causative relationship between spinal stenosis and gut microbiota. Conclusion: This analysis demonstrated a possible causal relationship between certain particular gut microbiota and the occurrence of spinal stenosis. Further studies focused on the mechanism of gut microbiota-mediated spinal stenosis can lay the groundwork for targeted prevention, monitoring, and treatment of spinal stenosis.

Smoking may increase the usage of antidepressant: evidence from genomic perspective analysis.

This study uses the two-sample Mendelian randomization (TSMR) method to explore the causal relationships between smoking initiation (SMKI), never smoking (NSMK), past tobacco smoking (PTSMK), and the usage of antidepressants (ATD). Single-nucleotide polymorphisms (SNPs) with genome-wide significance (P < 5E-08) related to SMKI, NSMK, and PTSMK were selected from the genome-wide association study (GWAS) database as instrumental variables (IVs). The main method, inverse variance weighted (IVW), was utilized to investigate the causal relationship. The results demonstrated a positive causal relationship between SMKI and ATD use, where SMKI leads to an increase in ATD use. Conversely, NSMK and PTSMK showed a negative causal relationship with ATD use, meaning that NSMK and PTSMK lead to a reduction in ATD use. Additionally, sensitivity analysis showed that the results of this study were robust and reliable. Using the TSMR method and from a genetic perspective, this study found that SMKI leads to an increase in ATD use, while NSMK and PTSMK reduce ATD use.

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study.

Background: Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships. Methods: Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables' (IVs) assumptions. Results: Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], p = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy. Conclusion: Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.