Two-sample Mendelian Randomization Research Articles

Causal relationship between immune cells and hypopituitarism: bidirectional Mendelian randomization study

Hypopituitarism, one or more pituitary hormones inefficiently produced by the anterior pituitary or released from the posterior pituitary to adapt to the needs of the organism. Existing epidemiological data show that immune-mediated diffuse infiltration of the anterior pituitary is important in the development of hypopituitarism. However, the precise connection between immune cells and hypopituitarism remains unclear. This study aimed to elucidate the potential causal links between the 731 immune cell types and hypopituitarism risk. Based on data from a genome-wide association study (GWAS), a bidirectional two-sample Mendelian Randomization (MR) analysis was performed using five methods to explore the potential influence of immune cell phenotypes on hypopituitarism. Sensitivity analyses were conducted to examine the robustness of these findings. Our findings support that B cells, T cells, Tregs, dendritic cells, monocytes, and myeloid cells each have a bidirectional influence on hypopituitarism. One B-cell phenotype was associated with increased hypopituitarism risk, while two B-cell phenotypes play a protective role in hypopituitarism. Moreover, seven T-cell phenotypes demonstrate significant protective properties on hypopituitarism. Seven Tregs were associated with increased hypopituitarism risk. Furthermore, one monocyte was identified to be significantly associated with hypopituitarism risk. In addition, reverse MR analysis revealed that hypopituitarism was positively associated with 30 additional immune cell phenotypes and negatively associated with 17 immune cells. Our investigation shed light on the intricate potential relationship between immune cells and hypopituitarism via genetic methods, underscoring the immune-mediated pathway in hypopituitarism pathogenesis, thereby offering valuable insights for future clinical investigations.

A two-step, two-sample Mendelian randomization analysis investigating the interplay between gut microbiota, immune cells, and melanoma skin cancer.

This study aims to rigorously explore the potential causal relationships among gut microbiota (GM), immune cells, and melanoma skin cancer among participants from Europe, where this disease exhibits significant prevalence and profound societal impact. Using the genome-wide association analysis database, a double-sample Mendelian randomization (MR) analysis was drawn upon to investigate GM, immune cells, and melanoma skin cancer. The inverse variance weighted approach was applied to estimate the causal connections among these variables. A two-step MR analysis was employed to quantitatively gauge the impact of immune cells mediated GM on melanoma skin cancer. To address potential sources of bias, such as pleiotropy and heterogeneity, multiple analytical techniques were integrated. The MR analysis pinpointed 6 GM taxa related to either an augmented or declined risk of late-stage melanoma skin cancer. In the same vein, 32 immune cell phenotypes were noticed as correlates with modified risk of melanoma skin cancer. Our study also implies that the probable association between GM and melanoma could be facilitated by 5 immune cell phenotypes. The findings of our study underline certain GM taxa and immune cells as potential influencers on the onset and development of melanoma skin cancer. Importantly, our results spotlight 5 immune cell phenotypes as potential agents mediating this association.

Genetic determinants of cerebrospinal fluid metabolites and risk of Guillain-Barré syndrome: A bidirectional two-sample Mendelian randomization study.

This study aims to investigate the potential causal relationship between cerebrospinal fluid (CSF) metabolites and Guillain-Barré syndrome (GBS) using a bidirectional two-sample Mendelian randomization (MR) approach. Publicly available summary data from genome-wide association studies (GWAS) were utilized for comprehensive analysis. The CSF metabolite GWAS summary data were extracted from a GWAS conducted by Panyard et al encompassing 338 CSF metabolites in European participants (n = 291). GWAS summary statistics for GBS were obtained from the FinnGen consortium (n = 215,931) comprising European populations. The primary method for MR analysis was the inverse variance weighted method. Various sensitivity analyses were conducted to assess the heterogeneity and pleiotropy of the findings. In the forward MR analysis, we identified a causal relationship between 15 CSF metabolites, including ribitol levels (odds ratio = 3.833, 95% confidence interval: 1.949-7.540, P = 9.87E-05), and the risk of developing GBS. In the reverse MR analysis, we found a causal relationship between GBS and 21 CSF metabolites, including gamma-glutamylphenylalanine levels (odds ratio = 0.934, 95% confidence interval: 0.904-0.966, P = 7.10E-05). No evidence of heterogeneity or horizontal pleiotropy was found in the MR analysis. Our findings suggest that the identified CSF metabolites and metabolic pathways can serve as valuable biomarkers for clinical screening and prevention of GBS. They may also be considered as candidate molecules for future research into the underlying mechanisms and for selecting drug targets.

Genetically predicted serum ferritin mediates the association between inflammatory cytokines and non-alcoholic fatty liver disease

ObjectiveInvestigating the causal relationship between inflammatory cytokines and Non-alcoholic fatty liver disease(NAFLD) and identifying and quantifying the role of serum ferritin as a potential mediator.MethodsGenetic summary statistics were derived from open genome-wide association study (GWAS) databases. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the relationship between inflammatory cytokines (8,293 individuals) and NAFLD (8,434 cases, 770,180 controls). Furthermore, we used two-step MR to quantitate the proportion of the effect of serum ferritin-mediated inflammatory cytokines on NAFLD. In this study, we primarily utilized inverse-variance-weighted Mendelian randomization (MR-IVW) and reverse MR analysis methods, while other methods were also performed for sensitivity analysis, false discovery rate (FDR) <0.0012 as statistical significance in MR analyses.ResultsOur results indicated that high levels of Eotaxin, regulated upon activation normal T cell expressed and presumably secreted(RANTES), Interleukin-2(IL-2), macrophage migration inhibitory factor(MIF), tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) and Stem cell factor(SCF) were associated with increased risks of NAFLD, while high Cutaneous T cell-attracting chemokine(CTACK) and Interleukin-16(IL-16) levels that reduced the risk of NAFLD.The proportion of genetically predicted NAFLD mediated by ferritin was 2.1%(95% CI = 1.39%−5.61%).ConclusionIn conclusion, our study identified a causal relationship between inflammatory cytokines and NAFLD, with a small proportion of the effect mediated by ferritin, but a majority of the effect of inflammatory cytokines on NAFLD remains unclear. Further research is needed on additional risk factors as potential mediators.

Genetically proxied liability to migraine and risk of intracranial aneurysm and subarachnoid hemorrhage.

Observational studies have reported inconsistent relationships between migraine and the risk of intracranial aneurysm and subarachnoid hemorrhage (SAH). To determine whether genetic liability to migraine is associated with risk of intracranial aneurysm and aneurysmal SAH. This study was designed as a two-sample Mendelian randomization (MR) analysis. Genetic associations with migraine were obtained from a large-scale meta-analysis of five population and clinic-based genome-wide association studies of migraine (102,084 cases and 771,257 controls of European ancestry). Genetic associations with intracranial aneurysm and SAH were obtained from a meta-analysis of 22 population-based genome-wide association studies (7495 cases and 71,934 controls of European ancestry). Findings were corroborated by sensitivity analyses and replicated in an independent sample of combined cases of intracranial aneurysm and SAH (3529 cases and 234,948 controls of Asian ancestry from the Biobank Japan and China Kadoorie Biobanks). In secondary analyses, we investigated the outcomes of extracranial aneurysm in the FinnGen and UK Biobank cohorts (up to 7466 combined cases of thoracic and abdominal aortic aneurysm). Genetic liability to migraine was associated with increased risk of the combined outcome of unruptured intracranial aneurysm and SAH (odds ratio [OR] of outcome per doubling in migraine liability 1.19, 95% confidence interval [CI] 1.06-1.35; p = 0.005). This finding was replicated in an independent sample (OR 1.15, 95% CI 1.02-1.30; p = 0.027), and there were similar associations across the component outcomes of unruptured intracranial aneurysm (OR 1.20, 95% CI 1.01-1.42; p = 0.035) and SAH (OR 1.18, 95% 1.04-1.33; p = 0.008). These findings were consistent in sensitivity analyses robust to violations of the MR assumptions. In reverse MR analyses, genetic liability to intracranial aneurysm was not associated with migraine (OR 1.03, 95% CI 0.99-1.07; p = 0.141). In a secondary analysis, there were similar associations of genetic liability to migraine with all forms of aortic aneurysm (OR for combined thoracic and aortic aneurysm 1.18, 95% CI 1.10-1.27; p = 8.49 × 10-6). Genetic liability to migraine was associated with increased risk of intracranial and extracranial aneurysms, supporting a causal relationship between liability to migraine and these traits. Further work is needed to identify the biological mechanisms and clinical relevance of these findings.

Causal association between remnant cholesterol level and risk of cardiovascular diseases: a bidirectional two sample mendelian randomization study

Serum lipids have been associated with an increased risk of various cardiovascular diseases (CVDs) in several observational studies, but the causal inference between the remnant cholesterol (RC) levels and several CVDs risk has not been established. The purpose of this study was to investigate whether there is a causal relationship between RC levels and risk of developing CVDs by a bidirectional two-sample Mendelian randomization (TSMR) analysis. One TSMR analysis was performed using the publicly released large-scale genome-wide association study (GWAS) data. Inverse variance weighted (IVW) method was chosen as the main analysis method, and MR-Egger, weighted median, simple mode, and weighted mode were used as supplementary methods. We conducted a series of sensitivity analyses to assess the robustness of the main results, including the Cochran’s Q test, MR-Egger intercept test, leave-one-out sensitivity analysis, and funnel plot. The main IVW method revealed that genetically predicted serum level of RC is significantly associated with an increased risk of developing ischemic heart disease (OR = 1.409, 95%CI = 1.284–1.546, P value = 4.753E-13), unstable angina pectoris (OR = 1.621, 95%CI = 1.398–1.880, P value = 1.672E-10), myocardial infarction (OR = 1.526, 95%CI = 1.337–1.741, P value = 3.771E-10), cardiac arrest (OR = 1.595, 95%CI = 1.322–1.924, P value = 1.076E-06), heart failure (OR = 1.086, 95%CI = 1.009–1.169, P value = 0.028), hypertension (OR = 1.089, 95%CI = 1.043–1.136, P value = 9.458E-05), major coronary heart disease (CHD) events (OR = 1.515, 95%CI = 1.376–1.669, P value = 3.217E-17), coronary atherosclerosis (OR = 1.388, 95%CI = 1.231–1.564, P value = 7.739E-08), cardiac arrhythmias (OR = 1.067, 95%CI = 1.008–1.130, P value = 0.025), and atrial fibrillation and flutter (OR = 1.122, 95%CI = 1.039–1.211, P value = 0.003). Additionally, the causal associations between the RC levels and these CVDs remained significant after correcting for the false discovery rate (all P value < 0.05). However, this study did not find any significant association of RC with cardiomyopathy and pericarditis (both P value > 0.05). Heterogeneity existed in the IVs of RC and ischemic heart disease, unstable angina pectoris, myocardial infarction, heart failure, hypertension, major CHD events, cardiomyopathy, coronary atherosclerosis, cardiac arrhythmias and atrial fibrillation and flutter using the Cochran’s Q test (all P value < 0.05). Moreover, there was no horizontal pleiotropy in this study (all P value > 0.05). The leave-one-out sensitivity analyses showed that the causal effects between RC level and CVDs (except for heart failure, cardiomyopathy, pericarditis and cardiac arrhythmias) are not driven by a single SNP. The funnel plots showed that there is no obvious potential bias in our study. In the replication analysis, the genetically predicted RC levels were positively associated with a 43.12% higher risk of coronary artery disease. This present study supported the causal link between RC and heightened the risk of CVDs, indicating that RC-lowering treatment might be effective in preventing CVDs.

Causal association between plasma metabolites and diverse autoimmune diseases: a two-sample bidirectional mendelian randomization study

Causal association between plasma metabolites and diverse autoimmune diseases: a two-sample bidirectional mendelian randomization study

Exploring the mediating role of immune cells in the pathogenesis of IgA nephropathy through the inflammatory axis of gut microbiota from a genomic perspective.

IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 + + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.

Identifying the genetic association between severe autoimmune type 2 diabetes and the risk of focal epilepsy

BackgroundObservational studies suggested a bidirectional relationship between severe autoimmune type 2 diabetes and focal epilepsy. However, it remains debated whether and in which direction a causal association exists. This genetics-based study aimed to explore the relationships of severe autoimmune type 2 diabetes (T2DM) and focal epilepsy outcomes with two sample Mendelian randomization (TSMR) method.MethodsGenetic instruments were obtained from large-scale genome-wide meta-analysis of severe autoimmune T2DM (Ncase = 452, Ncontrol = 2,744), and focal epilepsy (Ncase = 929, Ncontrol = 212,532) of European ancestry. A series of analyses were performed to select eligible genetic instruments robustly associated with each of the traits using summary-level statistics. Inverse variance weighted was used for primary analysis, with alternative 11 MR methods. A scatter plot was utilized to illustrate the association between single nucleotide polymorphism (SNP) effects on the exposure and SNP effects on the outcome. The Wald ratio for individual SNPs and their cumulative effects was depicted using a forest plot. And diagnostics and sensitivity analyses were used to evaluate if the causal estimates are robust to violations of MR underlying assumptions, including pleiotropy, heterogeneity assessment, and leave-one-out analysis. Then the results were validated using CURATED database of DisGeNET platform.ResultsFor forward analysis, genetic predisposition to severe autoimmune T2DM was associated with an increased risk of focal epilepsy (Inverse variance weighted (IVW) method: OR = 1.11, 95% CI = 1.03-1.18, p = 0.012). For reverse analysis, there was no enough instrument variables of focal epilepsy on severe autoimmune T2DM. Further, the interrelation between severe autoimmune T2DM and focal epilepsy was demonstrated via variant-disease association network analysis using the instrument SNPs.DiscussionThis MR study supports a causal link between severe autoimmune T2DM and focal epilepsy. More effort should be made to screen seizure in severe autoimmune T2DM, unravel its clinical implications, and explore its role as a putative modifiable risk factor.

Causal correlations between inflammatory proteins and heart failure: A two-sample Mendelian randomization analysis.

Inflammation plays a critical role in both the development and progression of heart failure (HF), which is a leading cause of morbidity and mortality worldwide. However, the causality between specific inflammation-related proteins and HF risk remains unclear. This study aims to investigate the genetically supported causality between inflammatory proteins and HF using a two-sample Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data of 91 inflammation-related proteins as exposures from the SCALLOP Consortium (14,824 participants), alongside outcome GWAS summary statistics from FinnGen (29,218 cases/381,838 controls) and HERMES (47,309 cases/930,014 controls) for HF, to conduct a two-sample MR analysis. For each inflammatory protein, instrumental variables (IVs) were chosen following the three foundational assumptions of the MR analysis, requiring a minimum of three qualifying single nucleotide polymorphisms (SNPs) each with a P<5e-8. Associations between inflammatory proteins and HF were assessed through inverse-variance weighted (IVW), MR-Egger regression, weighted median and weighted mode analysis. The reliability and validity of the results were evaluated by examining heterogeneity, horizontal pleiotropy, leave-one-out analysis, meta-analysis and reverse MR analysis. Heterogeneity refers to the variation in results across different genetic variants. Horizontal pleiotropy occurs when a genetic variant influences multiple traits through different biological pathways. Addressing both heterogeneity and horizontal pleiotropy is crucial for ensuring the reliability and interpretability of MR results. Our analysis identified associations between three inflammatory proteins and HF risk. Matrix metalloproteinase-1 (MMP-1) (OR, 1.09; 95% CI, 1.00-1.18; P=0.04) and TNF-beta (OR, 1.05; 95% CI, 1.01-1.09; P=0.01) were positively associated with HF risk in FinnGen. In contrast, urokinase-type plasminogen activator (uPA) was inversely associated with HF risk in both FinnGen (OR, 0.85; 95% CI, 0.78-0.92; P=3.27e-5) and HERMES (OR, 0.93; 95% CI, 0.87-0.99; P=0.03). No evidence of heterogeneity and horizontal pleiotropy was observed in the MR analysis, indicating the robustness of our findings. A meta-analysis further supported this association, indicating a reduced risk (OR, 0.89; 95% CI, 0.81-0.98; P=0.02). No reverse causality was found between HF and these three inflammatory proteins (P>0.05 for all). This study provides genetically supported evidence of the causal association of specific inflammatory proteins with HF risk. The positive association of MMP-1 and TNF-beta with HF suggests their roles in disease pathogenesis, whereas the inverse association of the uPA indicates its potential protective effect. Our findings highlight the potential of targeting specific inflammatory pathways as a therapeutic strategy for HF.

Association and mediation pathways of maternal hyperglycaemia and liability to gestational diabetes with neonatal outcomes: A two-sample Mendelian randomization study.

Maternal hyperglycemia is linked to adverse neonatal outcomes. However, current evidence was insufficient for mechanistic pathways. We aim to use two-sample Mendelian randomization (MR) to obtain a comprehensive understanding of the causal association and mediation pathways. Genetic variants of fasting glucose (FG), insulin sensitivity index (ISI), glycated haemoglobin (HbA1c), gestational diabetes mellitus (GDM) and type 2 diabetes (T2D) were used as instruments (N = 50 404-898 130). The associations with offspring birthweight, gestational duration, spontaneous preterm and post-term birth were assessed by the inverse-variance weighted method, using summary statistics of European genome-wide association studies (N = 131 279-210 248). Sensitivity analyses, including multivariable MR removing pleiotropic effect from maternal body mass index (BMI), assessed the robustness. Mediation via placental weight and maternal hypertension were assessed via a two-step MR design. FG (0.46 SD per mmol/L, 95% confidence interval [95% CI]: 0.32, 0.61) and GDM liability (0.18 SD per log odds, 95% CI: 0.08, 0.18) were positively associated with birthweight, with consistent findings for HbA1c, T2D liability and ISI. These associations were mediated by placental weight (proportion mediated: 32.8% to 77.7%). Higher HbA1c, GDM and T2D liability were associated with preterm birth (odds ratios for GDM: 1.07, 95% CI: 1.01, 1.14) and shorter gestational duration, whilst the association for T2D attenuated after adjusted for maternal BMI and gestational hypertension. Maternal hyperglycemia is associated with higher birthweight (possibly indicating macrosomia), mediated via increased placental growth. GDM and T2D liability are related to preterm birth, whilst the association for T2D liability is driven by maternal adiposity.

Obesity and risk for liver disease: a two-sample Mendelian randomisation study.

The associations between obesity and liver diseases are complex and diverse. To explore the causal relationships between obesity and liver diseases, we applied two-sample Mendelian randomisation (MR) and multivariable MR analysis. The data of exposures (BMI and WHRadjBMI) and outcomes (liver diseases and liver function biomarker) were obtained from the open genome-wide association study database. A two-sample MR study revealed that the genetically predicted BMI and WHRadjBMI were associated with non-alcoholic fatty liver disease, liver fibrosis and autoimmune hepatitis. Obesity was not associated with primary biliary cholangitis, liver failure, liver cell carcinoma, viral hepatitis and secondary malignant neoplasm of liver. A higher WHRadjBMI was associated with higher levels of biomarkers of lipid accumulation and metabolic disorders. These findings indicated independent causal roles of obesity in non-alcoholic fatty liver disease, liver fibrosis and impaired liver metabolic function rather than in viral or autoimmune liver disease.

Causal effects of plasma proteome on intervertebral disc degeneration: a comprehensive mendelian randomization study.

Intervertebral disc degeneration (IVDD) considerably impacts global disability and quality of life. Although potential links between plasma proteins and IVDD exist, their causal correlation remains undefined. This study explored the causal links between plasma proteins and IVDD employing genome-wide association study data. For this observational study, summary statistics for plasma proteins were derived from an Icelandic population, paralleled with genome-wide data on IVDD obtained from the FinnGen consortium. Using two-sample Mendelian randomization, we assessed the causal relationship between 4,907 plasma proteins and IVDD. Standard sensitivity analyses encompassing heterogeneity, pleiotropy, and leave-one-out cross-validation tests confirmed the stability and robustness of the findings. Subsequently, through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein interaction analyses, we delved into the functional interrelation among identified plasma proteins. A causal association with IVDD was identified for 47 plasma proteins; myoneurin, intersectin 1, and eukaryotic translation initiation factor 4 gamma 3 maintained significant correlations post multiple correction tests (P < 1.02 × 10- 5), influencing IVDD development positively. GO/KEGG pathway analyses confirmed that multiple pathways may be involved in IVDD development. The study underscores the causal correlation between plasma protein levels and IVDD risk. These identified proteins could emerge as unique biomarkers for IVDD, contributing to its predictive measures. The findings further our understanding of IVDD pathomechanisms and prospective therapeutic targets.

The causal association between COVID-19 and ischemic stroke: a mendelian randomization study

BackgroundCurrent observational data indicates that ischemic stroke (IS) affects a significant proportion of people with COVID-19. The current study sought to evaluate the causal relationship between COVID-19 and IS.MethodsA two-sample Mendelian randomization (2 S-MR) approach was used to probe the relationship between genetic determinants of three COVID-19 parameters (SARS-CoV‐2 infection, COVID-19 hospitalization, and severe COVID-19) and the incidence of IS based on genome-wide association studies (GWAS) data. Using this 2 S-MR technique, expression quantitative trait loci (eQTL) and GWAS studies were further assessed for overlap to identify common causative genes associated with severe COVID-19 and IS.ResultsIVW approaches indicated the genetic variants linked to COVID-19 hospitalization (OR 1.04, 95% CI 1.01–1.08, p = 0.023) and severe COVID-19 (OR 1.03, 95% CI 1.01–1.05, p = 0.007) were both significantly linked to greater odds of IS. In contrast, there was no causal association between genetic SARS-CoV-2 infection susceptibility and the occurrence of IS (OR 0.99, 95% CI 0.92–1.06, p = 0.694). Ten shared causal genes (TNFSF8, CFL2, TPM1, C15orf39, LHFPL6, FAM20C, SPAG9, KCNJ2, PELI1, and HLA-L) were established as possible mediators of the interplay between severe COVID-19 and the development of IS, with these genes primarily being enriched in immune-related and renin-angiotensin-aldosterone system pathways.ConclusionThese findings indicate a possible causative relationship between IS risk and COVID-19 severity, offering crucial new information for managing COVID-19 patients. Promising options for therapeutic therapies for severe COVID-19 complicated by IS include the common genes found in the present study.

Causal associations of tea consumption on risk of pancreatic adenocarcinoma and the mediating role of vascular endothelial growth factor D levels.

Tea is one of the most widely consumed beverages in the world. However, the association between tea and risk of pancreatic adenocarcinoma remains controversial. This study aimed to investigate the causal relationship between tea consumption and risk of pancreatic adenocarcinoma and to explore their mediating effects. The two-sample Mendelian randomisation (MR) analysis showed an inverse causal relationship between tea intake and pancreatic adenocarcinoma (OR: 0·111 (0·02, 0·85), P < 0·04). To examine the mediating effects, we explored the potential mechanisms by which tea intake reduces the risk of pancreatic adenocarcinoma. Based on the oral bioavailability and drug-like properties in Traditional Chinese Medicine Systems Pharmacology database, we selected the main active ingredients of tea. We screened out the fifteen representative targeted genes by Pharmmapper database, and the gene ontology enrichment analysis showed that these targeted genes were related to vascular endothelial growth factor (VEGF) pathway. The two-step MR analysis of results showed that only VEGF-D played a mediating role, with a mediation ratio of 0·230 (0·066, 0·394). In conclusion, the findings suggest that VEGF-D mediates the effect of tea intake on the risk of pancreatic adenocarcinoma.

Evaluating the causal effects between Grave’s disease and diabetes mellitus: a bidirectional Mendelian randomization study

BackgroundGraves’ disease (GD) is an autoimmune disease associated with an increased incidence of other autoimmune diseases. To investigate the causality between GD and Diabetes mellitus (DM), we designed bidirectional two-sample Mendelian randomization (MR) and multivariable MR (MVMR) studies.MethodsSingle-nucleotide polymorphisms (SNPs) associated with GD, thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid-stimulating hormone (TSH), type 1 diabetes (T1D), and type 2 diabetes (T2D) were obtained from the IEU Open GWAS and FinnGen biobank databases. For the forward MR study, we used GD (sample size = 458,620) as the exposure and T1D (sample size = 520,580) and T2D (sample size = 211,766) as the outcomes. Next, high risk of T1D and T2D were used as exposure variables, and GD was used as the outcome variable for the reverse MR analysis. Finally, MVMR analysis was conducted to investigate the probable relationship between DM and indicators for thyroid function like TPO, Tg, and TSH. The inverse variance weighting (IVW) was used as the main method. Finally, the heterogeneity and sensitivity were assessed.ResultsThere were 27, 88, and 55 SNPs associated with GD, T1D, and T2D, respectively. A significant causal connection between higher genetic liability of GD and the risk of T2D (OR [95% CI] = 1.059 [1.025–1.095], P = 5.53e-04) was found in the forward MR analysis. Comparatively, the significant causal relationship between higher genetic liability of GD and the risk of T1D was not demonstrated (OR [95% CI] = 0.998[0.927,1.074], P=0.949). However, reverse MR suggested that there was a genetic susceptibility to T1D that increased the likelihood of developing GD (OR [95% CI] = 1.173[1.117,1.231], P = 1.913e-10), while T2D did not (OR [95% CI] = 0.963 [0.870–1.066], P = 0.468). Furthermore, there was inadequate evidence to suggest that abnormal TSH, TPO, and Tg levels increase the risk of incident T1D or T2D in individuals with GD. MVMR revealed no causal relationship among Tg, TSH, TPO, T1D, or T2D.ConclusionThere was no increased risk of T1D with an increase in genetic susceptibility to GD, although higher genetic susceptibility to T1D has been shown to be associated with increased risk of developing GD. A unidirectional causal relationship between the genetic liability for GD and increased risk of T2D was observed using MR analyses. MVMR analysis showed no statistically relevant causality between the genetic liability for TSH, TPO, or Tg and the risk of either T1D or T2D.

The association between breast cancer and lung cancer: a bidirectional Mendelian randomization study.

With increasing life spans, breast cancer (BC) survivors may face the possibility of developing second primary cancer (SPC), which can considerably shorten survival. Lung cancer (LC) is a common SPC among BC survivors. This study explored the association between these two cancers through Mendelian randomization (MR) analysis. A bidirectional two-sample MR analysis was conducted with BC genome-wide association study (GWAS) data from the Breast Cancer Association Consortium (BCAC) included 228,951 individuals and the GWAS summary statistics from the Transdisciplinary Research in Cancer of the Lung (TRICL) of LC included 112,781 individuals. The IVW method and MR-RAPS method showed a causal effect of overall BC on lung adenocarcinoma (LUAD) (IVW: OR = 1.060, 95% CI = 1.008-1.116, P = 0.024; MR-RAPS: OR = 1.059, 95% CI = 1.005-1.116, P = 0.033), which indicated that patients with BC had an increased risk of LUAD. However, there is no strong evidence for a causal effect of LUAD on BC. Our study revealed a causal effect of BC on second primary LUAD, suggesting that we should intensify screening for second primary LC in BC survivors. Early intervention and treatment for patients with second primary LC are needed to reduce mortality in BC survivors.

Changes in resting-state functional connectivity of large-scale brain networks in bulimia nervosa: evidence from causal analysis.

Bulimia nervosa (BN) has been observationally linked to the functional connectivity (FC) of large-scale brain networks, but the biological mechanisms remain unclear. This study used two-sample Mendelian randomization (MR) with genetic variations as instrumental variables (IVs) to explore potential causal relationships between FC and BN. Summary data from genome-wide association studies (GWAS) involving 2,564 individuals were analyzed to identify genetically predicted BN. Functional magnetic resonance imaging parameters and materials were sourced from the UK Biobank. The variables underwent independent component analysis processing by the database to generate the final GWAS dataset. Various methods, including MR Pleiotropy RESidual Sum and Outlier, MR Egger, and weighted median, were employed to detect heterogeneity and pleiotropy, with inverse variance weighting serving as the principal estimation method (P < 0.05). The FC imaging-derived phenotypes revealed that BN exerted a causal influence on the FC between large-scale networks, including the visual network, default mode network (DMN), frontoparietal network, somatosensory network (SSN), and ventral attention network. Additionally, BN had a causal impact on the within-network FC of both the DMN and SSN. The study provides evidence that BN leads to further changes in FC patterns within and between large-scale brain networks.

Association Between Circulating Vitamin K Levels, Gut Microbiome, and Type 1 Diabetes: A Mendelian Randomization Study

Background/Objectives: Nutritional deficiencies have been proposed as possible etiological causes for autoimmune diseases, among which type 1 diabetes (T1D). Vitamin K (VK) has potentially positive effects on type 2 diabetes, but its role on T1D in humans remains largely unknown. We aimed to examine the presence of a causal association between VK and T1D using a Mendelian randomization (MR) approach. Methods: Genetic variants from a genome-wide association study (GWAS) for VK (N= 2138 Europeans) were used as instruments in our two-sample MR study to investigate whether circulating VK levels are causally associated with the risk of T1D in a large European T1D GWAS cohort (18,942 cases/520,580 controls). Through a multivariable MR (MVMR), the effects of both VK and specific gut microbiota on T1D were investigated given that the gut microbiome synthesizes VK. Results: We found that changes in levels of circulating VK did not affect T1D risk in our univariate two-sample MR, but this study had limited power to detect small effects of VK (OR for T1D of less than 0.8). However, our MVMR indicated a suggestive association of VK with the risk of T1D adjusting for two different gut microbiome populations. Conclusions In conclusion, VK levels are unlikely to significantly affect the risk of T1D, but small effects cannot be excluded, and the role of gut microbiome in this association should be further investigated.

Causal association between Parkinson’s disease and cancer: a bidirectional Mendelian randomization study

BackgroundPrevious observational research has indicated a correlation between Parkinson’s disease (PD) and multiple cancers; but the causality remains unclear. Thus, we utilized Mendelian randomization (MR) analysis to explore the potential causal link between PD and various cancers.MethodsWe conducted a bidirectional two-sample Mendelian randomization (TSMR) of genetic variants associated with PD and 14 types of cancers. Summary statistics on PD and 14 types of cancers were obtained from the International Parkinson’s Disease Genomics Consortium and the study by Sakaue et al. The primary method employed was inverse variance weighted (IVW), complemented by multiple sensitivity analyses to evaluate heterogeneity and pleiotropy. The false discovery rate (FDR) was employed to control the false positive rate of multiple hypothesis testing.ResultsFollowing rigorous sensitivity analyses and corrections, our findings revealed suggestive associations between PD and certain cancers. We observed that PD decreases the risk of gastric cancer and colorectal cancer (OR = 0.936, 95% CI = 0.881–0.995, p = 0.034, P FDR = 0.239; OR = 0.955, 95% CI = 0.912–0.999, p = 0.046, P FDR = 0.215), while increasing the risk of breast cancer (OR = 1.043, 95% CI = 1.004–1.084, p = 0.029, P FDR = 0.402). Notably, we found no evidence supporting a reverse causal relationship. Additionally, in the reverse pathway, skin cancer demonstrated a suggestive causal relationship with PD (OR = 0.913, 95% CI = 0.857–0.973, p = 0.005, P FDR = 0.066).ConclusionOur MR analysis provides evidence supporting unidirectional suggestive causal relationships between PD and certain cancers. These findings enrich our comprehension of the intricate interplay between PD and cancer, warranting further investigation into the underlying biological mechanisms.