Bidirectional Mendelian Randomization Analysis Research Articles

Causal effects of plasma metabolites on autoimmune hepatitis (AIH): a bidirectional two-sample mendelian randomization study

Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10− 5,OR: 0.62, 95% CI 0.49–0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67–1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.

No causal relationship serum lipids on age-related hearing loss based on Mendelian randomized evidence

ObjectivesPresbycusis, or age-related hearing loss (ARHL) has been a common disability disease among the elderly population. It is particularly essential to identify the underlying role of related risk factors for ARHL diagnosis and treatment. Observational studies have shown that cardiovascular disease may be a factor in ARHL. Serum lipids are a key risk factor for cardiovascular disease. Therefore, it may be a potentially influencing factor for elderly deafness. We conduct the study to analyze the causal relationship between serum lipids and European elderly deafness. DesignUsing genetic variation data related to serum lipids (total cholesterol levels [TCL], total triglycerides levels [TGL], and lipoprotein fractions, including apolipoprotein A1 levels [APOA1L], apolipoprotein B levels [APOBL], high-density lipoprotein cholesterol levels [HDL], and low-density lipoprotein cholesterol levels [LDL]) as instrumental variables, the outcome events were summarized from the genome-wide association study data of elderly deafness, and Mendelian randomization (MR) analysis was used in our analysis. The relationship between serum lipids levels and ARHL was analyzed using five methods, including inverse variance weighted, weighted mode, MR-Egger, weighted median, and simple mode. The study aims to use bidirectional MR analysis. ResultsAmong all 5 methods, no significant causal effects were found between serum lipids (TCL OR = 0.936, p = .488; TGL OR = 0.955, p = 0.657; APOA1L OR = 0.864, p = .061; APOBL OR = 0.979, p = .786; HDL OR = 0.998, p = .979; LDL OR = 1.089, p = .281) and presbycusis. ConclusionThe findings of MR causal inference analysis did not support the causal relationship between presbycusis and serum lipids, including cholesterol, triglycerides, and lipoprotein fractions (APOA1L, APOBL, HDL and LDL).

Genetic predisposition to thyrotoxicosis and onset of knee osteoarthritis.

Thyroid hormones have actions on cartilage, whereas the association between thyroid hormone related diseases and osteoarthritis (OA) are unclear. This study aims to investigate the association between thyrotoxicosis and OA. Summary-level genetic data of thyrotoxicosis were obtained from FinnGen cohorts (nCase = 10,569, nControl = 762,037). Summary-level data of OA were obtained from a large-scale genome-wide association study of UK Biobank (nCase = 40,659, nControl = 756,338). Single nucleotide polymorphisms (SNPs) robustly associated with thyrotoxicosis or OA were used as genetic instruments. A two-sample bidirectional Mendelian randomization (MR) analysis was designed to assess the effect of genetic predisposition of thyrotoxicosis on OA risk, as well as the reverse their relationship. The causal effect was estimated by Inverse-variance weighted method, with weighted median and MR-Egger as supplementary methods. Genetic predisposition of thyrotoxicosis was associated with the onset of knee OA (autoimmune hyperthyroidism: odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03-1.07, FDR < 0.001; thyrotoxicosis: OR: 1.05, 95% CI: 1.02-1.08, FDR = 0.016; thyrotoxicosis with diffuse goitre: OR: 1.04, 95% CI: 1.02-1.07, FDR = 0.003; other and/or unspecified thyrotoxicosis: OR: 1.05, 95% CI: 1.02-1.09, FDR = 0.003), whereas thyrotoxicosis was not associated with hip OA. In reverse MR analysis, genetic predisposition to OA was not associated with thyrotoxicosis. No pleiotropy was identified in the MR analyses. Sensitivity analyses indicated the robustness of the MR estimates. This study provides MR evidence supporting causal association of thyrotoxicosis with knee OA in European population, whereas OA may have no causal effects on thyrotoxicosis.

Vitamin D Levels and Temporomandibular Disorders: A Bidirectional Two-Sample Mendelian Randomization Analysis.

Growing researches explore vitamin D's role in temporomandibular disorders (TMDs), but the link between vitamin D and TMDs remains debated. To clarify the causal relationship, we conducted a Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS). The GWAS dataset of vitamin D (GWAS ID: ukb-d-30890_irnt; sample size: 329247) was obtained from the IEU Open GWAS project. And that of TMDs (GWAS ID: finn-b-TEMPORO; sample size: 134280), initiated on August 25th, 2017 and publicly released on December 18th, 2023, was extracted from the FinnGen dataset, whose cases were diagnosed based on the revised International Classification of Diseases, 10th Edition (ICD-10) code K07.6. Both datasets were obtained from the European population. According to three assumptions of MR analysis, a bi-directional MR analysis was performed to measure the causal relationship, with Inverse variance weighted (IVW) as the primary method and MR Egger and Weighted median as supplement. Moreover, diverse sensitivity analyses, including Cochran's Q test, MR Egger intercept, Mendelian randomized polymorphism RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis, were used to verify the stability of the findings. The MR analysis supported causal effects of vitamin D levels on TMDs risks within the European population using IVW method [odds ratio = 1.316; 95% confidence interval = 1.086 to 1.595; P = 0.005], supported by MR Egger and Weighted median. While there was no indication that TMDs have a direct impact on vitamin D levels [β: -0.00738, standard error = 0.00665; P = 0.568]. The study revealed that within the European population higher levels of vitamin D led to higher risks of developing temporomandibular disorders, but found no obvious evidence that TMDs are causally associated with vitamin D. The conclusion should be cautiously interpreted, given the selection bias of TMDs patients sample.

Bidirectional Mendelian randomization analysis of plasma lipidome and psychiatric disorders

BackgroundEvidence from observational studies and clinical experiments suggests a close association between plasma lipidome and psychiatric disorders. However, the causal relationship between plasma lipidome and psychiatric disorders remains insufficiently determined. Plasma lipidome are relatively easy to measure and regulate clinically, and they play a crucial role in neuronal signal transduction, making them a focus of interest as potential therapeutic targets for psychiatric disorders. MethodsIn this study, we utilized the latest Finnish population-based genome-wide association study (GWAS) data on 179 lipid species. We downloaded data on five psychiatric disorders from the IEU database, including schizophrenia, bipolar disorder, depression, autism from the PGC consortium, and anxiety disorder from the Neale lab. Using two-sample bidirectional Mendelian randomization (MR) analysis, we assessed the relationship between these 179 lipid species and the risk of the five psychiatric disorders. To validate the assumptions of Mendelian randomization, we conducted tests for horizontal pleiotropy and heterogeneity. ResultsAfter applying FDR correction to assess the relationship between 179 lipid species traits and the risk of five psychiatric disorders, our analysis provided evidence of a causal relationship specifically between genetic susceptibility in the plasma lipidome and bipolar disorder. This relationship notably involves eight phosphatidylcholines (PCs) and two sterols, with PCs displaying a dual and complex role in the disorder. Reverse Mendelian randomization (MR) analysis did not reveal a significant causal impact of psychiatric disorders on the plasma lipidome. LimitationsDespite using two-sample bidirectional Mendelian randomization analysis, the complex biological pathways and potential confounding factors may still affect the accuracy of the causal relationships. The impact of genetic variations on the lipidome and psychiatric disorders may involve multiple mechanisms, which cannot be fully elucidated in this study. ConclusionThis study identified a causal relationship between genetic susceptibility in plasma lipidome and bipolar disorder, indicating that plasma lipidome may influence the risk of psychiatric disorders and providing direction for exploring them as potential intervention targets. The findings not only deepen our understanding of the etiology of psychiatric disorders but also provide a critical theoretical foundation for future clinical interventions and prevention strategies, potentially contributing to the development of novel therapeutic approaches.

Exploring the complex relationship between attention deficit hyperactivity disorder and the immune system: A bidirectional Mendelian randomization analysis

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that can be accompanied by alterations in immune markers. However, the intricate nature of the association between ADHD and immune markers remains insufficiently elucidated. To explore the currently ambiguous causal relationship between ADHD and the immune system, we performed a bidirectional Mendelian randomization (MR) analysis of immune cell traits and ADHD under the randomized inverse variance weighting (IVW) method based on genome-wide association study (GWAS) summary data. We found ADHD increased the level of 3 immune cell traits including myeloid dendritic cells (β = 0.28, P = 0.008), monocyte (β = 0.25, P = 0.024) and granulocyte (β = 0.2, P = 0.042). We also identified 1 trait which belongs to B cell panel was a risk factor (odds ratio (OR) = 1.07, P = 0.001) for ADHD onset. Other 5 traits including CD14+ monocyte (OR = 0.98, P = 0.002), immature myeloid-derived suppressor cells (MDSC) (OR = 0.98, P = 0.003), monocyte MDSC (OR = 0.95, P = 0.005), CD33br HLA DR+ (OR = 0.97, P = 0.021) and basophil (OR = 0.96, P = 0.022) were protective factors for ADHD. Here we identified a range of causal relationships extending from ADHD to immune cell traits, underscoring the complex interaction patterns between ADHD and the immune system. Enhanced interventions for protective and risk factors may be beneficial in the prevention and treatment of ADHD.

Bidirectional Two-Sample Mendelian Randomization Analysis Reveals Causal Associations Between Modifiable Risk Factors and Fibromyalgia.

This study aims to investigate the potential causal effects of modifiable risk factors on Fibromyalgia (FM). Genetic variants associated with 34 exposure factors were obtained from Genome-wide association studies (GWAS). Summary statistics for FM were acquired from the FinnGen consortium. Bidirectional Mendelian randomization (MR) analysis was conducted between all exposures and outcomes. The inverse-variance weighted (IVW) method was employed as the primary estimation technique. Heterogeneity and pleiotropy were assessed using MR-PRESSO global test, the weighted median, Cochran's Q statistic and MR-Egger. Depression (OR=2.087, 95% CI: 1.466-2.971), alcohol consumption (OR=1.489, 95% CI: 1.094-2.028), body fat percentage (OR=1.524, 95% CI: 1.153-2.013) and body mass index (BMI) (OR=1.542, 95% CI: 1.271-1.872) were associated with an increased risk of FM among genetically susceptible individuals. Conversely, higher education level (OR=0.404, 95% CI: 0.297-0.549), longer years of education (OR=0.489, 95% CI: 0.290-0.825) and higher household income (OR=0.328, 95% CI: 0.215-0.502) were protective against FM. Additionally, rheumatoid arthritis (OR=1.138, 95% CI: 1.061-1.221) and ankylosing spondylitis (OR=1.079, 95% CI: 1.021-1.140) were identified as important risk factors for FM. This MR study unveiled a complex causal relationship between modifiable risk factors and FM. Psychosocial factors significantly increase the odds of FM, while obesity and some autoimmune diseases that frequently coexist with FM demonstrate causal associations. Additionally, lifestyle habits such as alcohol consumption are causally related to FM. Further investigation is needed to determine whether risk factors contribute to the pathogenesis of FM through mechanisms involving central sensitization, inflammatory, and hyperalgesia. This study enhances our understanding of the factors that drive FM onset and progression, offering valuable insights for future targeted prevention and treatment strategies.

Genomic Correlation, Shared Loci, and Causal Relationship Between Bullous Pemphigoid and Atopic Dermatitis: A Large-Scale Genome-Wide Cross-Trait Analysis.

Bullous pemphigoid (BP) and atopic dermatitis (AD) are currently thought to be tightly related, yet studies of the mechanisms of co-morbidities are lacking. We obtained GWAS data for BP (N = 376,274) and AD (N = 796,661) from the Finnish Genetic Research Program dataset and the UK Biobank, separately. Then, the following four analyses were performed: (1) cross-trait linkage disequilibrium score regression (LDSC) to assess the genetic correlation between BP and AD, (2) cross-phenotype association analysis (CPASSOC) to identify multiple effector loci shared by BP and AD, (3) transcriptome-wide association study (TWAS) to determine whether their cross-organizational expression patterns share genes with a common biological mechanism of relevance, and (4) bidirectional Mendelian randomization (MR) analysis to assess bidirectional causal effects of BP and AD. We found a positive genetic association between BP and AD (rg = 0.5476, p = 0.0495) as well as identified four pleiotropic loci and 59 common genes affecting BP and AD. Bidirectional MR analysis suggested that BP promotes the risk of AD. We revealed a genetic link between BP and AD, which is associated with biological pleiotropy and causality. Awareness of the association between BP and AD helps dermatologists manage patients with these illnesses.

Causal Relationship Between Childhood Obesity and Sleep Apnea Syndrome: Bidirectional Two-Sample Mendelian Randomization Analysis.

Childhood obesity has become a global pandemic, leading to a range of diseases. Childhood obesity appears to be associated with an increased prevalence of sleep apnea syndrome. Sleep apnea is an inestimable risk factor for thrombosis, hypertension, cardiomyopathy and many other diseases. Therefore, exploring the relationship between childhood obesity and sleep apnea syndrome will help to understand the potential link between the two and provide research directions for future disease prevention and treatment. However, no studies have confirmed whether there is a causal relationship between childhood obesity and sleep apnea syndrome. The IEU OpenGWAS project provided the GWAS-aggregated data for childhood obesity and sleep apnea syndrome. Inverse-variance weighted (IVW) was used as the main method to evaluate the causal relationship between childhood obesity and sleep apnea syndrome. Single nucleotide polymorphisms (SNPs) were regarded as instrumental variables, and the screening threshold was P <5.0×10-6. Leave-one-out method was performed to confirm the robustness of the results. IVW analysis confirmed a causal relationship between genetic susceptibility to childhood obesity and an increased risk of sleep apnea syndrome [odds ratio (OR)=1.12, 95% confidence interval (CI): 1.02-1.23, P=0.016]. However, two-sample MR results also showed no causal relationship between genetic susceptibility to sleep apnea syndrome and an increased risk of childhood obesity (OR=1.50, 95% CI: 0.95-2.38, P=0.083). The intercept of MR-Egger regression was close to 0, which implies that there are no confounding factors in the analysis to affect the results of two-sample MR analysis. The leave-one-out results show that the bidirectional two-sample MR analysis results were robust. There is a causal relationship between genetic susceptibility to childhood obesity and increased risk of sleep apnea syndrome. People with a history of childhood obesity should pay more attention to physical examination to early prevention and management of sleep apnea syndrome.

Identifying the Genetic Associations Between Diabetes Mellitus and the Risk of Vitiligo.

While increasing observational studies have suggested an association between diabetes mellitus (DM) and vitiligo, the causal relationship and possible mechanism remain unclear. Publicly accessible genome-wide association study (GWAS) was utilized to conduct a bidirectional two-sample Mendelian randomization (MR) analysis. GWAS data for diabetes and vitiligo were obtained from the UK Biobank Consortium (20203 cases and 388756 controls) and the current GWAS data with largest cases (GCST004785, 4680 cases and 39586 controls) for preliminary analysis, respectively. Inverse variance weighting (IVW) was used as the main analysis method. Several sensitivity analyses were utilized to test the pleiotropy or heterogeneity. To explore the possible mechanism of gene-generating effects represented by the final instrumental variables in the analysis, enrichment analysis was conducted using the DAVID and STRING database. IVW method showed a significant genetic causal association between DM and vitiligo (OR = 1.20, 95% CI: 1.08-1.33, PIVW = 0.0009). Diabetes subtype analysis showed that T2D (type 2 diabetes) were associated with an increased risk of vitiligo (OR = 1.13, 95% CI: 1.00-1.27, PIVW = 0.0432). Sensitivity analysis further confirmed the robustness of the results. The enrichment analysis revealed that the genetic inducing effects of diabetes mellitus on vitiligo were primarily about pancreatic secretion and protein digestion and absorption pathway. Our findings provide genetic evidence that there is a notable association between T2D and an elevated risk of vitiligo in European populations. This result may explain why the co-presentation of T2D and vitiligo is often seen in observational studies, and emphasize the significance of vigilant monitoring and clinical evaluations for vitiligo in individuals diagnosed with T2D. The aberrant glucose and lipid metabolism and the primary nutrient absorption disorder of vitiligo brought on by diabetes may be the potential mechanisms behind this association.

Effect of the Antibody-mediated Immune Responses on COPD, Asthma, and Lung Function: A Mendelian Randomization Study

IntroductionThe precise cause of antibody-mediated immune responses on chronic obstructive pulmonary disease (COPD), asthma, and lung function remains unclear. We characterized the relationship between antibody-mediated immune responses to COPD, asthma, and lung function, ultimately achieve the prevention or treatment. MethodsWe obtained summary data from published genome-wide association studies, including antibody-mediated immune responses, COPD, asthma, forced expiratory volume in the first second (FEV1), forced expiratory volume (FVC), and FEV1/FVC. Bidirectional two-sample mendelian randomization (MR) analysis was used to assess causal relationships of antibody-mediated immune responses, COPD, asthma, FEV1, FVC, and FEV1/FVC. ResultsA total of 20 antibody-mediated immune responses were identified have a significant causal effect on COPD, asthma, FEV1, and FVC, with six exhibiting reverse causality. Importantly, the results of the five MR analyses were almost identical with respect to the causal effect of anti-polyomavirus 2 IgG seropositivity and varicella zoster virus glycoprotein E and I antibody levels on the risk of COPD, asthma, FEV1, and FVC. ConclusionsThis study contributes to existing knowledge by investigating the causal relationship between antibody-mediated immune responses and respiratory conditions, including COPD, asthma, and lung function, using a two-sample MR design. The key findings can aid in identifying individuals at risk of these conditions and facilitate early prevention and diagnosis.

Immune cells mediate the causal pathway linking circulating complements to cancer: A Mendelian randomization study.

The role of complement in cancer remains controversial. Whether immune cells and inflammatory factors mediate the pathway from complement to cancer has not been fully elucidated. We conducted bidirectional Mendelian randomization (MR) analysis to explore the causal association between complement components and cancer. Meta-analysis was conducted to enhance the robustness of the results. We further explored the mediation roles of immune cells and inflammatory factors in these associations. Our study identified causal associations between 11 complement components and 12 types of cancer. Furthermore, we identified five immune cells as potential mediators: BAFF-R on IgD + CD38- naive B cell mediated 7.434% of the increased risk for liver cancer from C3; CD4 on CD39 + activated CD4 regulatory T cell mediated 12.384% of the increased risk for biliary tract cancer from CD93; CD25 + + CD45RA + CD4 not regulatory T cell and Basophil %CD33dim HLA DR- CD66b- mediated 7.721% and 7.986% of the increased risk of colorectal cancer from MASP1, respectively; CD45RA on resting CD4 regulatory T cell mediated 11.444% of the increased risk of skin cancer from MASP1. This study revealed the causal relationships between complement components and certain cancers, with five immune cells as potential mediators.

Exploring causal association between functional/structural connectivity and major depression disorder: A bidirectional Mendelian randomization study

ObjectivesPrior observational studies have suggested a correlation between major depressive disorder (MDD) and communication imbalances within the resting-state brain network (RSN), but the causal relationship remains unclear. This research uses Mendelian randomization (MR) analysis to explore the potential causal effects between functional connectivity (FC), structural connectivity (SC) and MDD. MethodsTwo-sample bidirectional MR analysis was employed in this study. Inverse variance weighted (IVW) was used to explore the causal relationship between the FC/SC and MDD, with various methods such as MR-Egger to conduct sensitivity analyses. ResultsThe IVW analysis results showed that higher genetic predicted dorsal attention network FC, limbic network SC, and dorsal attention network SC were associated with an increased risk of MDD (β: 15.08, 95%CI: 5.89–24.27, p = 0.001; β: 3.79, 95%CI: −0.22-7.8, p = 0.034; β: 9.89, 95%CI: 0.88–18.90, p = 0.031). Reverse MR analysis demonstrated that a genetically predicted elevated risk of MDD was associated with reduced frontal parietal network FC (β: −0.00046, p = 0.041). ConclusionsThe study suggests a causal relationship between the FC and SC within specific RSNs and the risk of MDD. Abnormalities in the dorsal attention network FC/SC and the limbic network SC were risk factors for MDD. The FC abnormality of the frontal parietal network may be the downstream influence following the MDD onset. Further investigation is needed to determine the potential utility of these neuroimaging markers in the prevention of MDD or the evaluation of treatment efficacy.

The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.

Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method. We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10-5 as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy. The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p=.130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P=.300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p=.019). Moreover, the investigation of reverse causalities did not reveal significant results. The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.

Investigation of the causal relationship between cholelithiasis and Parkinson's disease: A bidirectional Mendelian randomization study.

Parkinson's disease (PD) and cholelithiasis are a huge public health burden. Although observational studies have suggested a potential link between PD and cholelithiasis, the causal relationship between the two remains uncertain. To address this gap, we performed a two-sample bidirectional Mendelian randomization analysis using genetic tools. Genome-wide association study summary statistics for all traits were obtained from publicly available databases. We used strict control steps in instrumental variable selection to screen for single nucleotide polymorphisms (SNPs) from summary-level genome-wide association studies. In addition, all F-statistics were >10, indicating no weak instrumental bias. The inverse variance weighting (IVW) method was the primary method used to assess causal associations. Four other MR methods (MR-Egger, Weighted Median, Simple mode, and Weighted mode) were also used to complement IVW. Various sensitivity tests were also performed to assess reliability: (1) Cochrane's Q test for assessing heterogeneity, (2) MR-Egger intercept test and MR-PRESSO global test for assessing horizontal multiplicity, and (3) leave-one-out sensitivity test for determining stability. We selected a total of 30 SNPs as instrumental variables. It was demonstrated that cholelithiasis had a causal effect on the risk of PD (OR = 1.146, 95% CI: 1.062-1.236, p < 0.001) in IVW method. The results of our analysis revealed an increased risk effect of cholelithiasis against PD, which may give light on new approaches to PD prevention and therapy.

Causal relationship between circulating immune cells and gastric cancer: a bidirectional Mendelian randomization analysis using UK Biobank and FinnGen datasets.

The role of immune cells in cancer pathogenesis remains controversial due to conflicting reports, potentially arising from various confounding factors. Emerging evidence suggests that cancer can also influence immune cell populations and functions, making it challenging to investigate their causal relationship. Traditional observational studies often fail to eliminate all confounding factors and are prone to reverse causality. Therefore, we employ Mendelian randomization (MR) to determine the causal relationship between immune cells and cancer, as this method can identify causal relationships independent of confounding factors and avoid reverse causality. Genome-wide association study (GWAS) summary statistics on immune traits, encompassing 310 immune cell phenotypes, were obtained from 3,757 European individuals, with peripheral blood immune cells tested using flow cytometry. GWAS summary statistics for gastric cancer were derived from 476,116 European individuals across two large-scale biobanks: the UK Biobank and FinnGen. Gastric cancer was identified by the International Classification of Diseases, 9th Revision (ICD-9), and 10th Revision (ICD-10) codes. Significant single nucleotide polymorphisms (SNPs) for immune traits were extracted at a threshold of P<1×10-5, while a threshold of P<5×10-8 was used for gastric cancer GWAS data. Linkage imbalance-based clumping was performed to obtain independent SNPs, and those with F<10 were excluded to mitigate weak instrument bias. Phenoscanner V2 was used to exclude SNPs directly associated with potential confounders or outcomes. Two-sample MR was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. A false discovery rate (FDR) correction was used to reduce the likelihood of type 1 errors. In addition, we conducted MR-Egger intercept tests and Cochran's Q tests. The numbers of CD4-CD8- T cells and IgD-CD27- B cells were positively correlated with the development of gastric cancer, with odds ratios (ORs) of 1.15 [95% confidence interval (CI), 1.07-1.24; P<0.001; PFDR=0.041; IVW method] and 1.07 (95% CI, 1.03-1.11; P=0.001; PFDR=0.187; IVW method), respectively. However, the percentage of IgD+CD24- B cells in lymphocytes were negatively associated with the development of gastric cancer (OR =0.90; 95% CI, 0.84-0.96; P=0.002; PFDR=0.187; IVW method). MR analysis of the above three immune cell phenotypes showed no significant heterogeneity or horizontal pleiotropy. In the reverse MR analysis, gastric cancer was not causally associated with any of the immune cell phenotypes. Circulating CD4-CD8- T cells and IgD-CD27- B cells are positively correlated with the development of gastric cancer, while the percentage of IgD+CD24- B cells in lymphocytes are negatively correlated. These findings provide insight into the relationship between immune cells and gastric cancer pathogenesis and may serve as a basis for the development of immunotherapies for gastric cancer.

A multi-level investigation of the genetic relationship between gastroesophageal reflux disease and lung cancer.

Observational studies have revealed a potential association between gastroesophageal reflux disease (GERD) and lung cancer (LC), but the genetic role in their comorbidity have not been fully elucidated. This study aimed to comprehensively dissect the genetic link underlying GERD and LC. Using large-scale genome-wide association study (GWAS) data, we investigated shared genetic architecture between GERD and LC. Our analyses encompassed genetic correlation, cross-trait meta-analysis, transcriptome-wide association studies (TWASs), and the evaluation of the causality though a bidirectional Mendelian randomization (MR) analysis with sufficient sensitivities. We identified a significant genome-wide genetic correlation between GERD and overall LC (rg =0.33, P=1.58×10-14), as well as across other subtype-specific LC (rg ranging from 0.19 to 0.39). After separating the whole genome into approximately 2,353 independent regions, 5 specific regions demonstrated significant local genetic correlation, with most significant region located at 9q33.3. Cross-trait meta-analysis revealed 22 pleiotropic loci between GERD and LC, including 3 novel loci (rs537160, rs10156445, and rs17391694). TWASs discovered a total of 49 genes shared in multiple tissues, such as lung tissues, esophagus muscularis, esophagus mucosa, and esophagus gastroesophageal junction. MR analysis suggested a significantly causal relationship between GERD and overall LC [odds ratio (OR) =1.34, 95% confidence interval (CI): 1.19-1.51], as well as other subtype-specific LC (OR ranging from 1.25 to 1.76). No evidence supports a significant causal effect of LC on GERD. Our findings suggest intrinsic genetic correlation underlying GERD and LC, which provides valuable insights for screening and management of LC in individuals with GERD.

Association between retinal nerve fiber layer thickness and psychiatric disorders: a mendelian randomization study

BackgroundRetinal nerve fiber layer thickness, as a new visual indicator that may help diagnose mental disorders, is gaining attention from researchers. However, the causal relationship between retinal nerve fiber layer thickness and mental disorders is still to be effectively proved.MethodsA bidirectional Two-sample Mendelian randomization analysis was utilized to analyse aggregated data from large-scale genome-wide association studies, we selected genetic loci for retinal nerve fiber layer thickness in independent retinal abnormalities and three prevalent psychiatric disorders (schizophrenia, depression, bipolar disorder) as instrumental variables. The Two-sample Mendelian randomization analysis was mainly performed by inverse variance weighting and weighted median method. The Cochran Q test and leave-one-out sensitivity were used to ensure the robustness of the results. The Mendelian random polymorphism residuals and outliers were used to detect single nucleotide polymorphism outliers, and MR-Egger intercept test was used to test single nucleotide polymorphism horizontal pleiotropy.ResultsIVW showed that retinal nerve fiber layer thickness was positively associated with schizophrenia (OR = 1.057, 95%CI: 1.000-1.117, P < 0.05), in the study of bipolar disorder, MR analysis also suggested a positive causal relationship between retinal nerve fiber layer thickness and bipolar disorder (OR = 1.025, 95%CI: 1.005–1.046, P < 0.05), which indicated possible causal relationships between retinal nerve fiber layer thickness and these two diseases. Depression (OR = 1.000143, 95%CI: 0.9992631–1.001024, P = 0.74) indicated no significant causal association. No reverse causal effects of psychiatric disorders on retinal nerve fiber layer thickness were found.ConclusionsA statistically significant causal relationship between retinal nerve fiber layer thickness and schizophrenia and bipolar disorder has been supported by genetic means, indicating RNFL has potential to aid in the diagnosis of schizophrenia and bipolar disorder.

Brain imaging traits and epilepsy: Unraveling causal links via mendelian randomization.

Epilepsy, a complex neurological disorder, is closely linked with structural and functional irregularities in the brain. However, the causal relationship between brain imaging-derived phenotypes (IDPs) and epilepsy remains unclear. This study aimed to investigate this relationship by employing a two-sample bidirectional Mendelian randomization (MR) approach. The analysis involved 3935 cerebral IDPs from the UK Biobank and all documented cases of epilepsy (all epilepsies) cohorts from the International League Against Epilepsy, with further validation through replication and meta-analyses using epilepsy Genome-Wide Association Studies datasets from the FinnGen database. Additionally, a multivariate MR analysis framework was utilized to assess the direct impact of IDPs on all epilepsies. Furthermore, we performed a bidirectional MR analysis to investigate the relationship between the IDPs identified in all epilepsies and the 15 specific subtypes of epilepsy. The study identified significant causal links between four IDPs and epilepsy risk. Decreased fractional anisotropy in the left inferior longitudinal fasciculus was associated with a higher risk of epilepsy (odds ratio [OR]: 0.89, p=3.31×10-5). Conversely, increased mean L1 in the left posterior thalamic radiation (PTR) was independently associated with a heightened epilepsy risk (OR: 1.14, p=4.72×10-5). Elevated L3 in the left cingulate gyrus was also linked to an increased risk (OR: 1.09, p=.03), while decreased intracellular volume fraction in the corpus callosum was correlated with higher epilepsy risk (OR: 0.94, p=1.15×10-4). Subtype analysis revealed that three of these IDPs are primarily associated with focal epilepsy (FE). Notably, increased L1 in the left PTR was linked to an elevated risk of hippocampal sclerosis (HS) and lesion-negative FE, whereas elevated L3 in the left cingulate gyrus was associated with HS-related FE. Our research offers genetic evidence for a causal link between brain IDPs and epilepsy. These results enhance our understanding of the structural brain changes associated with the onset and progression of epilepsy.

Relationship between serum vitamin D levels and thyroid- and parathyroid-related diseases: a Mendelian randomisation study.

Previous studies have indicated an association between vitamin D and thyroid- and parathyroid-related diseases. However, it remains unclear whether it is a cause of the disease, a side effect of treatment or a consequence of the disease. The Mendelian randomisation (MR) study strengthens the causal inference by controlling for non-heritable environmental confounders and reverse causation. In this study, a two-sample bidirectional MR analysis was conducted to investigate the causal relationship between serum vitamin D levels and thyroid- and parathyroid-related diseases. Inverse variance weighted, weighted median and MR-Egger methods were performed, the Cochran Q test was used to evaluate the heterogeneity and the MR-PRESSO and MR-Egger intercepts were utilised to assess the possibility of pleiotropy. The Bonferroni-corrected significance threshold was 0·0038. At the Bonferroni-corrected significance level, we found that vitamin D levels suggestively decreased the risk of benign parathyroid adenoma (OR = 0·244; 95 % CI 0·074, 0·802; P = 0·0202) in the MR analyses. In the reverse MR study, a genetically predicted risk of thyroid cancer suggestively increased the risk of elevated vitamin D (OR = 1·007; 95 % CI 1·010, 1·013; P = 0·0284), chronic thyroiditis significantly increased the risk of elevated vitamin D (OR = 1·007; 95 % CI 1·002, 1·011; P = 0·0030) and thyroid nodules was significantly decreased the vitamin D levels (OR = 0·991; 95 % CI 0·985, 0·997; P = 0·0034). The findings might be less susceptible to horizontal pleiotropy and heterogeneity (P > 0·05). This study from a gene perspective indicated that chronic thyroiditis and thyroid nodules may impact vitamin D levels, but the underlying mechanisms require further investigation.