Bidirectional Two-sample Mendelian Randomization Research Articles

Role of immune cells in mediating the effect of gut microbiota on Hashimoto's thyroiditis: a 2-sample Mendelian randomization study.

Hashimoto's thyroiditis (HT) is one of the most commonly encountered types of autoimmune thyroid disorders (AITDs), influenced by environmental factors, genetics, and the immune system. Previous research has shown a correlation between gut microbiota and HT, as well as the involvement of immune cells in its onset and progression. We aimed to investigate whether immune cells act as intermediaries in the causal relationship between gut microbiota and HT. In this study, we conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the relationship between gut microbiota and HT using data from genome-wide association studies (GWAS) and the MiBioGen study. Subsequently, MR analyses were performed to investigate the interactions between 731 immune cells and gut microbiota. Additionally, an MR analysis was performed to examine the association between HT and these 731 immune cells, using a GWAS dataset that included 3,757 European subjects. This approach provided insights into the impact of 22 million genetic variants on 731 immune cell signatures. There was a causal relationship between the increase in the number of 15 gut microbiota and HT. We observed that the genus Akkermansia, family Alcaligenaceae, family Desulfovibrionaceae, family Verrucomicrobiaceae, class Verrucomicrobiae, order Verrucomicrobiales, phylum Verrucomicrobia, class Alphaproteobacteria, order Desulfovibrionales, genus Ruminococcus torques group, genus Butyrivibrio, and genus Coprococcus3 were negatively correlated with HT. In addition, the genus Intestinimonas, genus Turicibacter, and genus Anaerostipes were positively correlated with HT. We identified EM CD4 + T cells as a mediator between the gut microbiota and HT. In conclusion, we presented causal associations between the EM CD4 + T cell-mediated gut microbiota and HT, as inferred from the MR findings derived from extensive aggregated GWAS data. Our research offers guidance and direction for treating and preventing HT.

Breast cancer and neoplasms of the thyroid gland: a bidirectional two-sample Mendelian randomization study.

With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90×10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately.

Multi-Ancestry Causal Association between Rheumatoid Arthritis and Interstitial Lung Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Rheumatoid arthritis (RA) is associated with diverse extra-articular manifestations, including interstitial lung disease (ILD). No previous studies have examined the bidirectional relationship between RA and ILD using the Mendelian randomization (MR) analyses. Therefore, we aimed to investigate this subject using a two-sample bidirectional MR method. Methods: We performed bidirectional two-sample MR using summary statistics from genome-wide association studies (GWASs). The data are publicly available, de-identified, and from European (EUR) and East Asian (EAS) ancestries. Results: A total of 474,450 EUR participants and 351,653 EAS participants were included for either forward or reverse MR analysis. In our primary analysis, we found significant evidence of an increased risk of ILD associated with RA among individuals of EUR ancestry (ORMR-cML = 1.08; 95% confidence interval [CI] = 1.03-1.14; p = 0.003) and EAS ancestry (ORMR-cML = 1.37; 95% CI = 1.23-1.54; p < 0.001). Additionally, the reverse MR showed significant evidence of an increased risk of RA associated with ILD among those of EUR ancestry (ORMR-cML = 1.12; 95% CI = 1.05-1.19; p < 0.001). However, only one instrumental variable was selected in the EAS ILD GWAS, and there was no increased risk of RA associated with ILD in those of EAS ancestry (ORMR-cML = 1.02; 95% CI = 0.91-1.14; p = 0.740). Conclusions: Our findings indicate that RA and ILD have a bidirectional causal inference when using the MR analysis of GWAS datasets. The findings are only relevant for genetic predisposition; thus, further research is needed to determine the impact of non-genetic predispositions.

Association between brain resting-state functional activities and migraine: a bidirectional mendelian randomization study

Researchers have conducted extensive research on the correlation between brain resting-state functional activities (RSFA) and migraine. However, we still do not fully understand the exact nature of the causal relationship between these RSFA and migraine. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the causal association between migraine and RSFA. We gathered summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging phenotypes. We employed various analytical methods for bidirectional two-sample MR analyses. This included inverse variance weighted, weighted median, MR Egger, and the constrained maximum likelihood approaches. We also conducted pleiotropy and heterogeneity analyses to evaluate the robustness and reliability. We found the functional connectivity between the default mode and the central executive network (OR = 1.39, p = 4.77 × 10−4, FDR corrected p value = 0.040) and the intensity of spontaneous brain activity in the calcarine or lingual gyrus within the visual network (OR = 0.74, p = 5.94 × 10−4, FDR corrected p value = 0.040) having a causal effect on the risk of migraine. Our MR analysis provided genetic support for these networks, which may play an important role in influencing migraine susceptibility.

Ischemic stroke and sarcopenia have an asymmetric bidirectional relationship based on a two-sample Mendelian randomization study.

We investigated the potential relationship between age-related conditions, particularly sarcopenia and ischemic stroke (IS), through a two-sample Mendelian randomization (MR) study. We conducted a two-sample bidirectional MR study to investigate the relationship between sarcopenia and stroke. Genetic instruments for sarcopenia were derived from the UK Biobank, while data on IS and its subtypes were obtained from the MEGASTROKE consortium. Inverse variance weighting (IVW) served as the primary analytical method. Additionally, heterogeneity and pleiotropy were assessed to ensure the robustness of the findings. The analysis indicates a negative correlation between appendicular lean mass (ALM) and small vessel stroke (SVS; OR = 0.790, 95% CI: 0.703-0.888, p < 0.001), a positive correlation with cardioembolic stroke (CES; OR = 1.165, 95% CI: 1.058-1.284, p = 0.002), and no causal relationship with any ischemic stroke (AIS) or large artery stroke (LAS). Additionally, SVS is negatively associated with right-hand grip strength (OR = 0.639, 95% CI: 0.437-0.934, p = 0.021), while AIS, LAS, and CES do not exhibit a causal relationship with grip strength. Furthermore, no causal relationship was identified between left-hand grip strength, usual walking pace, and IS or its subtypes. MR analysis reveals only a negative association between CES and usual walking pace (OR = 0.989, 95% CI: 0.980-0.998, p = 0.013), with no associations found between other IS subtypes and sarcopenia-related traits. This study demonstrates that a reduction in ALM and right-hand grip strength is associated with SVS, whereas decreased ALM may serve as a protective factor against CES. Conversely, our analysis suggests that CES can impact walking speed. Overall, these findings provide valuable insights into the prevention and treatment of these conditions.

The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

Causal role of 731 immune cells in diabetic nephropathy: a bi-directional two-sample Mendelian randomization study.

The primary cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN), and a growing body of research indicates that immunology plays a part in how DN develops into ESRD. Our objective is to identify causal relationships between various immune invading cells and DN to identify possible targets for immunotherapy. This study used a complete Mendelian randomization (MR) analysis with two samples to identify the underlying mechanism linking immune cell characteristics with DN. Using publicly available genetic data, we investigated the causal link between 731 immune cell profiles and DN risk. Included were four different types of immune systems: morphological parameters (MP), absolute cell (AC), relative cell (RC), and median fluorescence intensities (MFI). The results' robustness, heterogeneity, and horizontal pleiotropy were confirmed through extensive sensitivity analysis. Following FDR (False Discovery Rate correction method) correction, no statistically significant differences were observed; however, six immunophenotypes were shown to be significantly associated with DN risk at the 0.25 level. Only CD28+ CD4- CD8- T cells were identified as the protective immunophenotype (OR = 0.588, 95% CI 0.437-0.792, P = 4.71 × 10-4). Moreover, DN had no discernible impact on immunophenotyping after FDR correction. Surprisingly, three unadjusted phenotypes with low P values were discovered to be positively correlated with the risk of DN: CD20 on IgD- CD27- B cells (OR = 1.263, 95% CI 1.076-1.482, P = 4.22 × 10-3), CD8 on naive CD8 + T cells with Effector Memory (OR = 1.107, 95% CI 1.013-1.209, P = 2.40 × 10-2), and CD8 on Effector Memory CD8 + T cells (OR = 1.126, 95% CI 1.024-1.239, P = 1.46 × 10-2). Our findings provide a genetic basis for the association between immune cells and DN and should inform future clinical research.

Causal relationship between beta-2 microglobulin and B-cell malignancies: genome-wide meta-analysis and a bidirectional two-sample Mendelian randomization study.

Beta-2 microglobulin (β2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of β2M on B-cell malignancy risk, and vice versa, are limited. We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between β2M and B-cell malignancies and the underlying biological processes. The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with β2M. In the UKB, genetically predicted β2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in β2M; 95% confidence interval [CI]: 1.215-2.498; P = 3.00 × 10-3; FDR = 7.50× 10-3) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525-3.380; P = 5.15 × 10-5; FDR =2.58 × 10-4). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and β2M. In FinnGen, β2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; P = 8.28 × 10-4; FDR = 4.14 × 10-3), HL (OR: 1.581; 95% CI: 1.167-2.142; P = 3.13 × 10-3; FDR = 5.22 × 10-3), and FL (OR: 2.113; 95% CI: 1.292-3.455; P = 2.90 × 10-3; FDR = 5.22 × 10-3). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb β2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying β2M, DLBCL, and HL. Our findings suggested that elevated levels of β2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system.

Association of the gut microbiome and different phenotypes of COPD and asthma: a bidirectional Mendelian randomization study.

Mounting evidence has revealed the association between gut microbiota and both chronic obstructive pulmonary disease (COPD) and asthma; however, the causal association between gut microbiota and specific disease phenotypes remains to be determined. This study employed bidirectional two-sample Mendelian randomization (MR) analyses to investigate the potential causal relationship between gut microbiota and these conditions. The research utilized genome-wide association study (GWAS) data from the MiBioGen consortium for gut microbiota and the integrative epidemiology unit (IEU) Open GWAS for these conditions. Four MR analysis methods were employed: the inverse variance weighted (IVW) test, MR-Egger, weighted median, and weighted mode methods. The IVW method results are considered the primary findings. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy analysis, and leave-one-out analysis, were used to enhance robustness. Our MR study identified eight gut microbiota taxa potentially associated with the risk of different types of COPD and asthma. These include two taxa for early-onset COPD: Streptococcaceae [odds ratio (OR) = 1.315, 95% confidence interval (CI) = 1.071-1.616, P = 0.009] and Holdemanella (OR = 1.199, 95% CI = 1.063-1.352, P = 0.003); three for later-onset COPD: Acidaminococcaceae (OR = 1.312, 95% CI = 1.098-1.567, P = 0.003), Holdemania (OR = 1.165, 95% CI = 1.039-1.305, P = 0.009), and Marvinbryantia (OR = 0.814, 95% CI = 0.697-0.951, P = 0.009); one for allergic asthma: Butyricimonas (OR = 0.794, 95% CI = 0.693-0.908, P = 0.001); and two for non-allergic asthma: Clostridia (OR = 1.255, 95% CI = 1.043-1.511, P = 0.016) and Clostridiales (OR = 1.256, 95% CI = 1.048-1.506, P = 0.014).IMPORTANCEIndividuals with diverse phenotypes of chronic obstructive pulmonary disease (COPD) and asthma exhibit different responses to the conventional "one treatment fits all" approach. Recent research has revealed the significant role of the gut-lung axis in both COPD and asthma. However, the specific impact of gut microbiota on different subtypes of these conditions remains poorly understood. Our study has identified eight gut microbiota that may be associated with the risk of different types of COPD and asthma. These findings provide evidence suggesting a potential causal relationship between gut microbiota and various phenotypes of COPD and asthma. This offers a new perspective on the origins of different disease phenotypes and points toward future exploration of phenotype-specific and personalized therapies.

Investigating the Genetic Association of 40 Biochemical Indicators with Parkinson's Disease.

The mechanisms of Parkinson's disease (PD) are not fully understood, which hinders the development of effective therapies. Research indicates that lower levels of biochemical indicators like bilirubin, vitamin D, and cholesterol may elevate the risk of PD. However, clinical studies on abnormal levels of biochemical indicators in PD patients' circulation are inconsistent, leading to ongoing debate about their association with PD. Here, we investigate the genetic correlation between 40 biochemical indicators and PD using a bidirectional two-sample Mendelian randomization (MR) approach to uncover potential causal relationships. Data from genome-wide association studies (GWAS) were utilized, with genetic variations from specific lineages serving as instrumental variables (IVs). The methodology followed the STROBE-MR checklist and adhered to the three principal assumptions of MR. Statistical analyses employed methods including inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode. Biochemical indicators including albumin, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) showed significant associations with PD risk. Elevated levels of albumin (OR = 1.246, 95% CI 1.006-1.542, P = 0.043) and SHBG (OR = 1.239, 95% CI 1.065-1.439, P = 0.005) were linked to higher PD risk. Conversely, increased CRP levels (OR = 0.663, 95% CI 0.517-0.851; P = 0.001) could potentially lower PD risk. The robustness of the results was confirmed through various MR analysis techniques, including assessments of directional pleiotropy and heterogeneity using MR-Egger intercept and MR-PRESSO methods. This study systematically reveals, for the first time at the genetic level, the relationship between 40 biochemical indicators and PD risk. Our research verifies the role of inflammation in PD and provides new genetic evidence, further advancing the understanding of PD pathogenesis. The study shows a positive correlation between albumin and SHBG with PD risk and a negative correlation between CRP and PD risk. This study identifies for the first time that SHBG may be involved in the onset of PD and potentially worsen disease progression.

The Causal Relationship between Inflammatory Cytokines and Liver Cirrhosis in European Descent: A Bidirectional Two-Sample Mendelian Randomization Study and the First Conclusions.

Observational studies have highlighted the pivotal role of inflammatory cytokines in cirrhosis progression. However, the existence of a causal link between inflammatory cytokines and cirrhosis remains uncertain. In this study, we conducted a bidirectional Mendelian randomization (MR) analysis at a summarized level to illuminate the potential causal relationship between the two variables. This study utilized genetic variance in cirrhosis and inflammatory cytokines from a genome-wide association study (GWAS) of European descent. The MR-PRESSO outlier test, Cochran's Q test, and MR-Egger regression were applied to assess outliers, heterogeneity, and pleiotropy. The inverse variance weighted method and multiple sensitivity analyses were used to evaluate causalities. Furthermore, the validation set was used for simultaneous data validation. The inflammatory cytokine monocyte chemoattractant protein 3 (MCP-3) was supposedly associated with a greater risk of cirrhosis. And cirrhosis was significantly correlated with increased levels of hepatocyte growth factor (HGF). This study suggests that MCP-3 might be associated with the etiology of cirrhosis, while several inflammatory cytokines could potentially play a role in its downstream development. Additionally, the progression of cirrhosis was associated with elevated levels of HGF, suggesting a possible role for liver repair functions.

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.

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.

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.

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.

Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

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.

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.

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.