Bidirectional Two-sample Mendelian Randomization Research Articles

The association between testosterone, estradiol, estrogen sulfotransferase and idiopathic pulmonary fibrosis: a bidirectional mendelian randomization study

BackgroundThe causal relationships between testosterone, estradiol, estrogen sulfotransferase, and idiopathic pulmonary fibrosis (IPF) are not well understood. This study employs a bidirectional two-sample Mendelian Randomization (MR) approach to explore these associations.MethodsAll genetic data utilized in our study were obtained from the IEU Open GWAS project. For the MR analysis, we employed the inverse variance weighted (IVW), MR-Egger, and weighted median methods to assess the causal relationships. We also conducted a multivariate MR (MVMR) analysis, with adjustments made for smoking. To ensure the robustness of our findings, sensitivity analyses were conducted using Cochran’s Q test, MR-Egger regression, the MR-PRESSO global test, and the leave-one-out method.ResultsGenetically predicted increases in serum testosterone levels by one standard deviation were associated with a 58.7% decrease in the risk of developing IPF (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while an increase in serum estrogen sulfotransferase by one standard deviation was associated with a 32.4% increase in risk (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). No causal relationship was found between estradiol (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841) and the risk of IPF. Reverse MR analysis did not reveal any causal relationship between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018). The MVMR analysis demonstrated that the association between testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) and the risk of IPF persisted even after adjusting for smoking.ConclusionsIncreased serum levels of testosterone are associated with a reduced risk of IPF, while increased levels of serum estrogen sulfotransferase are associated with an increased risk. No causal relationship was found between estradiol and the development of IPF. No causal relationship was identified between IPF and testosterone, estradiol, or estrogen sulfotransferase.

Causal associations of hypothyroidism with frozen shoulder: a two-sample bidirectional Mendelian randomization study

BackgroundMany studies have investigated the association between hypothyroidism and frozen shoulder, but their findings have been inconsistent. Furthermore, earlier research has been primarily observational, which may introduce bias and does not establish a cause-and-effect relationship. To ascertain the causal association, we performed a two-sample bidirectional Mendelian randomization (MR) analysis.MethodsWe obtained data on “Hypothyroidism” and “Frozen Shoulder” from Summary-level Genome-Wide Association Studies (GWAS) datasets that have been published. The information came from European population samples. The primary analysis utilized the inverse-variance weighted (IVW) method. Additionally, a sensitivity analysis was conducted to assess the robustness of the results.ResultsWe ultimately chose 39 SNPs as IVs for the final analysis. The results of the two MR methods we utilized in the investigation indicated that a possible causal relationship between hypothyroidism and frozen shoulder. The most significant analytical outcome demonstrated an odds ratio (OR) of 1.0577 (95% Confidence Interval (CI):1.0057–1.1123), P = 0.029, using the IVW approach. Furthermore, using the MR Egger method as a supplementary analytical outcome showed an OR of 1.1608 (95% CI:1.0318–1.3060), P = 0.017. Furthermore, the results of our sensitivity analysis indicate that there is no heterogeneity or pleiotropy in our MR analysis. In the reverse Mendelian analysis, no causal relationship was found between frozen shoulders and hypothyroidism.ConclusionOur MR analysis suggests that there may be a causal relationship between hypothyroidism and frozen shoulder.

Causal relationships of grey matter structures in multiple sclerosis and neuromyelitis optica spectrum disorder: insights from Mendelian randomization.

Multiple sclerosis and neuromyelitis optica spectrum disorder are two debilitating inflammatory demyelinating diseases of the CNS. Although grey matter alterations have been linked to both multiple sclerosis and neuromyelitis optica spectrum disorder in observational studies, it is unclear whether these associations indicate causal relationships between these diseases and grey matter changes. Therefore, we conducted a bidirectional two-sample Mendelian randomization analysis to investigate the causal relationships between 202 grey matter imaging-derived phenotypes (33 224 individuals) and multiple sclerosis (47 429 cases and 68 374 controls) as well as neuromyelitis optica spectrum disorder (215 cases and 1244 controls). Our results suggested that genetically predicted multiple sclerosis was positively associated with the surface area of the left parahippocampal gyrus (β = 0.018, P = 2.383 × 10-4) and negatively associated with the volumes of the bilateral caudate (left: β = -0.020, P = 7.203 × 10-5; right: β = -0.021, P = 3.274 × 10-5) and putamen nuclei (left: β = -0.030, P = 2.175 × 10-8; right: β = -0.024, P = 1.047 × 10-5). In addition, increased neuromyelitis optica spectrum disorder risk was associated with an increased surface area of the left paracentral gyrus (β = 0.023, P = 1.025 × 10-4). Conversely, no evidence was found for the causal impact of grey matter imaging-derived phenotypes on disease risk in the opposite direction. We provide suggestive evidence that genetically predicted multiple sclerosis and neuromyelitis optica spectrum disorder are associated with increased cortical surface area and decreased subcortical volume in specific regions. Our findings shed light on the associations of grey matter alterations with the risk of multiple sclerosis and neuromyelitis optica spectrum disorder.

Gut microbiome and schizophrenia: insights from two-sample Mendelian randomization

Growing evidence suggests a potential link between the gut microbiome and schizophrenia. However, it is unclear whether the gut microbiome is causally associated with schizophrenia. We performed two-sample bidirectional Mendelian randomization to detect bidirectional causal relationships between gut microbiome and schizophrenia. Summary genome-wide association study (GWAS) datasets of the gut microbiome from the MiBioGen consortium (n = 18,340) and schizophrenia (n = 130,644) were utilized in our study. Then a cohort of sensitive analyses was followed to validate the robustness of MR results. We identified nine taxa that exerted positive causal effects on schizophrenia (OR: 1.08–1.16) and six taxa that conferred negative causal effects on schizophrenia (OR: 0.88–0.94). On the other hand, the reverse MR analysis showed that schizophrenia may increase the abundance of nine taxa (OR: 1.03–1.08) and reduce the abundance of two taxa (OR: 0.94). Our study unveiled mutual causal relationships between gut microbiome and schizophrenia. The findings may provide evidence for the treatment potential of gut microbiomes in schizophrenia.

Causality of Hashimoto's Thyroiditis to Thyroid Cancer: A 2-S Mendelian Randomization Study

BackgroundObservational studies have indicated an association between Hashimoto's thyroiditis (HT) and the risk of thyroid cancer (TC); however, the causality and direction of these effects in genetics remain unclear. Therefore, our study aims to investigate the relationship between genetic susceptibility to HT and TC through a bidirectional Mendelian randomization (MR) approach using twin samples. MethodsMR analysis was conducted using genetic instruments associated with HT, selected from a comprehensive genome-wide association meta-analysis involving a total of 756 000 individuals of European and East Asian descent. The data set for TC comprised 1.486 million individuals, including both European and East Asian populations. Single nucleotide polymorphisms closely linked to HT were derived from genome-wide association studies. Two-sample bidirectional MR analyses were applied to assess the causal association between HT and TC, using inverse-variance weighted methods, and MR Egger, weighted median, simple mode, and weighted mode. Furthermore, sensitivity analyses were conducted employing the MR-Egger regression model, weighted median method, MR pleiotropy residual sum and outlier, and leave-one-out technique. ResultsMR analyses revealed no evidence of a causal relationship between HT and TC in either European or East Asian populations (all P > .1). However, bidirectional MR analysis demonstrated a causal relationship between TC and HT in the European population (odds ratio = 1.0838, 95% confidence interval: 1.0346, 11 354, P = .000686). ConclusionThis MR analysis indicates a lack of evidence supporting an association between genetically predicted HT and the risk of developing TC. In contrast, there is evidence of a causal relationship between genetically predicted TC and HT.

A cause-effect relationship between uterine diseases and breast cancer: A bidirectional Mendelian randomization study

ObjectiveTo explore the cause-effect relationship between uterine diseases (UDs) and breast cancer (BC) and underlying mechanism of the cause-effect relationship, enhance understanding of the association between BC and UDs. MethodsA two-sample bidirectional Mendelian randomization (MR) analysis was conducted. We obtained summary statistics data from GWAS for BC, endometriosis, endometrial cancer (EC), uterine leiomyoma (UL), uterine polyps (UP), and cervical cancer (CC). Independent SNPs were selected as instrumental variables (IVs) for each disease. The inverse variance weighted (IVW) method was primary used for estimating the causal association between UDs and BC. To further evaluate the consistency and dependability of the results, we also utilized the weighted median, weighted mode, simple mode, and MR-Egger methods, along with sensitivity analyses. Furthermore, a supplementary analysis focusing on the variants linked to BC and UDs was conducted. This involved identifying corresponding genes and subsequently performing KEGG/GO analyses to investigate potential molecular mechanisms. ResultsThe results indicated significant associations between genetic susceptibility to endometriosis, EC, and UL with BC risk. The odds ratios (ORs) were as follows: endometriosis at 0.963 (95 % CI, 0.942–0.984; p = 7.11e-5), EC at 1.056 (95 % CI, 1.033–1.081; p = 2.39e-6), and UL at 1.027 (95 % CI, 1.006–1.048; p = 0.010). Conversely, the predisposition to BC inferred from genetic factors was markedly correlated with an elevated risk of EC indicated by an OR of 1.066 (95 % CI, 1.019–1.116; p = 0.006), and was correlated with UP risk (OR, 1.001,95 % CI, 1.000–1.002; p = 0.001).Sensitivity analyses provided weak evidence for these effects, suggesting that the study's outcomes are consistent and trustworthy. Further analysis of the genetic variants associated with BC, and these related genes are enriched in Cellular senescence, GnRH secretion, Phosphatidylinositol signaling system, and so on. ConclusionThis study corroborates the existence of a reciprocal causal relationship between BC and EC, as well as highlighting the substantial correlations between a genetic susceptibility to UL and endometriosis with BC. BC may exert their influence on EC and UP through Cellular senescence, GnRH secretion, and other pathways. These discoveries offer fresh perspectives on the genetic pathogenesis of BC and UDs, and can guide future experimental studies. Additionally, they lay down a groundwork for the development of tailored preventative and therapeutic strategies moving forward.

Abstract P322: Assessing the causal associations of obstructive sleep apnea syndrome and hypertension: a bidirectional two-sample Mendelian randomization study

Background: Obstructive sleep apnea syndrome (OSA) frequently coexists with hypertension, with 30% to 70% of OSA patients also having hypertension. Conversely, the incidence of OSA in hypertensive patients ranges from 30% to 50%. This study designs a bidirectional Mendelian randomization trial to explore the causal relationship between OSA and hypertension. Methods: The summary data for OSA were sourced from a recent large-scale genome-wide association study (GWAS) meta-analysis, which included 16,761 OSA patients and 201,194 European-ancestry controls from the Finnish biobank. Five SNPs were selected as instrumental variables (IVs) for OSA. The summary data for hypertension were obtained from the UK Biobank GWAS, which included 124,227 hypertension patients and 337,653 European-ancestry controls, making it the largest hypertension dataset in GWAS. From this dataset, 214 SNPs were selected as IVs for hypertension. Multiple MR methods, primarily the inverse variance weighted (IVW) method, were used for analysis. Sensitivity analyses of the MR results were performed using methods such as MR-Egger, and the F-statistic was used to evaluate the IVs. Results: OSA was associated with an increased risk of hypertension (OR=1.053, 95%CI 1.019-1.089, P<0.01), and hypertension was significantly associated with an increased risk of OSA (OR=1.812, 95%CI 1.354-2.425, P<0.001). There was heterogeneity in the bidirectional results (OSA → hypertension, P<0.001; hypertension → OSA, P<0.001), but no horizontal pleiotropy (OSA → hypertension, P=0.666; hypertension → OSA, P=0.556). The selected IVs for OSA and hypertension were strong (OSA-IVs F=14.695; hypertension-IVs F=39.624). Conclusion: This bidirectional MR analysis confirms the causal relationship between OSA and hypertension, with hypertension having a more pronounced effect on the incidence of OSA. OSA patients should regularly monitor their blood pressure and undergo routine physical examinations to detect hypertension early.

A commentary on 'Complex causal association between genetically predicted 731 immunocyte phenotype and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis' (Int J Surg. 2024 Mar 18).

A commentary on 'Complex causal association between genetically predicted 731 immunocyte phenotype and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis' (Int J Surg. 2024 Mar 18).

Causal Relationship Between Gut Microbiota and Chronic Obstructive Pulmonary Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

The associations between gut microbiota and chronic obstructive pulmonary disease (COPD) have gained increasing attention and research interest among scholars. However, it remains unclear whether gut microbiota serves as a causal factor for COPD or if it is a consequence of the disease. Therefore, we investigated the causal relationship between COPD and gut microbiota, with intention of providing novel insights and references for clinical diagnosis and treatment. Based on the genome-wide association study (GWAS) data, we employed MR-Egger regression, random-effects inverse variance-weighted (IVW) method, and weighted median method for bidirectional Mendelian randomization (MR) analysis. We conducted Cochran's Q test for heterogeneity assessment and performed multivariable analysis, sensitivity analysis, and heterogeneity testing to validate the reliability and stability of results. Utilizing MR analysis, mainly employing the IVW method, we detected a collective of 11 gut microbiota species that exhibited associations with COPD. Among them, Bacteroidia, family XIII, Clostridium innocuum group, Barnesiella, Collinsella, Lachnospiraceae NK4A136 group, Lachnospiraceae UCG004, Lachnospiraceae UCG010, and Bacteroidales were found to be protective factors for COPD. On the other hand, Holdemanella and Marvinbryantia were identified as risk factors for COPD. Individuals with elevated levels of Holdemanella exhibited a 1.141-fold higher risk of developing COPD compared to their healthy counterparts, and those with increased levels of Marvinbryantia had a 1.154-fold higher risk. Reverse MR analysis yielded no evidence indicating a causal relationship between gut microbiota and COPD occurrence. Our study established a causal link between 11 specific gut microbiota species and COPD, offering novel insights and valuable references for targeted therapies in the clinical management of COPD. However, our results were mainly based on the analysis of database, and further clinical studies are needed to clarify the effects of gut microbiota on COPD and its specific protective mechanism.

Specific blood metabolite associations with Gout: a Mendelian randomization study.

Gout, common metabolic disorders, have poorly understood links with blood metabolites. Exploring these relationships could enhance clinical prevention and treatment strategies. We applied bidirectional two-sample Mendelian randomization (MR) analysis, using data from a genome-wide association (GWAS) study of 486 blood metabolites. Gout data was obtained from FinnGen R8 (7461 gout and 221,323 control cases). We implemented the inverse variance-weighted (IVW) method for main analytical approach. Extensive heterogeneity, pleiotropy tests, leave-one-out analysis, and reverse MR were conducted to validate the robustness of our findings. Both Bonferroni and False Discovery Rate (FDR) corrections were used to adjust for multiple comparisons, ensuring stringent validation of our results. Initial MR identified 31 candidate metabolites with potential genetic associations to gout. Following rigorous sensitivity analysis, 23 metabolites as potential statistical significance after final confirmation. These included metabolites enhancing gout risk such as X-11529 (OR = 1.225, 95% CI 1.112-1.350, P < 0.001), as well as others like piperine and stachydrine, which appeared to confer protective effects. The analysis was strengthened by reverse MR analysis. Additionally, an enrichment analysis was conducted, suggesting that 1-methylxanthine may be involved in the metabolic process of gout through the caffeine metabolism pathway. Identifying causal metabolites offers new insights into the mechanisms influencing gout, suggesting pathways for future research and potential therapeutic targets.

Inflammatory bowel disease and white matter microstructure: A bidirectional Mendelian randomization study

BackgroundObservational studies have reported changes in the brain white matter (WM) microstructure in patients with inflammatory bowel disease (IBD); however, it remains uncertain whether the relationship between them is causative. The aim of this study is to reveal the potential causal relationship between IBD and WM microstructure through a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: We extracted genome-wide association study (GWAS) summary statistics for IBD and WM microstructure from published GWASs. Two-sample MR analysis was conducted to explore the bidirectional causal associations between IBD and WM microstructure, followed by a series of sensitivity analyses to assess the robustness of the results. Results: Although forward MR analysis results showed no evidence of causality from microstructural WM to IBD, reverse MR showed that genetically predicted IBD, consisting of ulcerative colitis and Crohn’s disease, has a significant causal effect on the orientation dispersion index (OD) of the right tapetum (β = −0.029, 95% CI = −0.045 to −0.013, p = 3.63 × 10−4). Further sensitivity analysis confirmed the robustness of the association. Conclusion: Our results suggested the potentially causal association of IBD with reduced OD in the right tapetum.

Exploring causal effects of sarcopenia on risk and progression of Parkinson disease by Mendelian randomization

Previous observational studies suggested that sarcopenia is associated with Parkinson disease (PD), but it is unclear whether this association is causal. The objective of this study was to examine causal associations between sarcopenia-related traits and the risk or progression of PD using a Mendelian randomization (MR) approach. Two-sample bidirectional MR analyses were conducted to evaluate causal relationships. Genome-wide association study (GWAS) summary statistics for sarcopenia-related traits, including right handgrip strength (n = 461,089), left handgrip strength (n = 461,026), and appendicular lean mass (n = 450,243), were retrieved from the IEU OpenGWAS database. GWAS data for the risk of PD were derived from the FinnGen database (4235 cases; 373,042 controls). Summary-level data for progression of PD, including progression to Hoehn and Yahr stage 3, progression to dementia, and development of levodopa-induced dyskinesia, were obtained from a recent GWAS publication on progression of PD in 4093 patients from 12 longitudinal cohorts. Significant causal associations identified in MR analysis were verified through a polygenic score (PGS)-based approach and pathway enrichment analysis using genotype data from the Parkinson’s Progression Markers Initiative. MR results supported a significant causal influence of right handgrip strength (odds ratio [OR] = 0.152, 95% confidence interval [CI] = 0.055–0.423, adjusted P = 0.0036) and appendicular lean mass (OR = 0.597, 95% CI = 0.440–0.810, adjusted P = 0.0111) on development of levodopa-induced dyskinesia. In Cox proportional hazard analysis, higher PGSs for right handgrip strength (hazard ratio [HR] = 0.225, 95% CI = 0.095–0.530, adjusted P = 0.0019) and left handgrip strength (HR = 0.303, 95% CI = 0.121–0.59, adjusted P = 0.0323) were significantly associated with a lower risk of developing levodopa-induced dyskinesia, after adjusting for covariates. Pathway enrichment analysis revealed that genome-wide significant single-nucleotide polymorphisms for right handgrip strength were substantially enriched in biological pathways involved in the control of synaptic plasticity. This study provides genetic evidence of the protective role of handgrip strength or appendicular lean mass on the development of levodopa-induced dyskinesia in PD. Sarcopenia-related traits can be promising prognostic markers for levodopa-induced dyskinesia and potential therapeutic targets for preventing levodopa-induced dyskinesia in patients with PD.

Potentially causal association between immunoglobulin G N-glycans and cardiometabolic diseases: Bidirectional two-sample Mendelian randomization study

BackgroundObservational studies support that altered immunoglobulin G (IgG) N-glycosylation and inflammatory factors are associated with cardiometabolic diseases (CMDs); nevertheless, the causality between them remains unclear. MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to systematically investigate the bidirectional causality between IgG N-glycans and nine CMDs in both East Asians and Europeans. ResultsIn the forward MR analysis, the univariable MR analysis presented suggestive causality of 14 and eight genetically instrumented IgG N-glycans with CMDs in East Asians and Europeans, respectively; the multivariable MR analysis showed that ten and 11 pairs of glycan-CMD associations were identified in East Asian and European populations, respectively. In the reverse MR analysis, based on East Asians and Europeans, the univariable MR analysis presented suggestive causality of seven and 12 genetically instrumented CMDs with IgG N-glycans, respectively; the multivariable MR analysis presented that six and five CMD-glycan causality were found in East Asian and Europeans, respectively. ConclusionsThe comprehensive MR analyses provide suggestive evidence of bidirectional causality between IgG N-glycans and CMDs. This work helps to understand the molecular mechanism of the occurrence/progression of CMDs, optimize existing and develop new strategies to prevent CMDs, and contribute to the early identification of high-risk groups of CMDs.

Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites

BackgroundUrolithiasis is a highly prevalent global disease closely associated with metabolic factors; however, the causal relationship between blood metabolites and urolithiasis remains poorly understood.MethodIn our study, we employed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between urolithiasis and metabolites. The random-effects inverse-variance weighted (IVW) estimation method was utilized as the primary approach, complemented by several other estimators including MR-Egger, weighted median, colocalization and MR-PRESSO. Furthermore, the study included replication and meta-analysis. Finally, we conducted metabolic pathway analysis to elucidate potential metabolic pathways.ResultsAfter conducting multiple tests for correction, glycerol might contribute to the urolithiasis and dehydroisoandrosterone sulfate (DHEA-S) might inhibit this process. Furthermore, several blood metabolites had shown potential associations with a causal relationship. Among the protective metabolites were lipids (dehydroisoandrosterone sulfate and 1-stearoylglycerol (1-monostearin)), amino acids (isobutyrylcarnitine and 2-aminobutyrate), a keto acid (acetoacetate) and a carbohydrate (mannose). The risk metabolites included lipids (1-palmitoylglycerophosphoethanolamine, glycerol and cortisone), a carbohydrate (erythronate), a peptide (pro-hydroxy-pro) and a fatty acid (eicosenoate). In reverse MR analysis, urolithiasis demonstrated a statistically significant causal relationship with butyrylcarnitine, 3-methyl-2-oxobutyrate, scyllo-inositol, leucylleucine and leucylalanine. However, it was worth noting that none of the blood metabolites exhibited statistical significance after multiple corrections. Additionally, we identified one metabolic pathway associated with urolithiasis.ConclusionThe results we obtained demonstrate the causal relevance between two metabolites and urolithiasis, as well as identify one metabolic pathway potentially associated with its development. Given the high prevalence of urolithiasis, further investigations are encouraged to elucidate the mechanisms of these metabolites and explore novel therapeutic strategies.

Mendelian randomization analysis reveals the combined effects of epigenetics and telomere biology in hematologic cancers

BackgroundTelomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks.MethodsThis study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR).ResultsOur research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007).ConclusionThe study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.

Relationship between serum neurofilament light chain protein and depression: A nationwide survey and Mendelian randomization study

BackgroundInvestigating the link between serum neurofilament protein (sNfL) levels and depression remains an area of limited understanding. This study explores the correlation in US adults and employs Mendelian randomization (MR) to ascertain causality. MethodsOur cross-sectional study analyzed data from participants aged 20 and above in the National Health and Nutrition Examination Survey (2013–2014). We employed a weighted multiple logistic regression model to examine the relationship between ln (sNfL) and depression. Restricted cubic splines (RCS) were used to visualize non-linear relationships. Stratified analyses examined associations between ln(sNfL) and depression in different subgroups. Subsequently, we conducted a two-sample bidirectional Mendelian randomization (MR) to assess the causal relationship between sNfL and depression. The inverse variance-weighted (IVW) method was utilized as the primary analysis. ResultsAmong 1765 participants (mean age 45.19 years; 49.37 % male), 166 had depression with a Patient Health Questionnaire (PHQ-9) score ≥ 10. After adjusting for covariates, a positive correlation remained between sNfL and depression (OR 1.511, 95 % CI: 1.050–2.175). RCS curves indicated a non-linear association, with a turning point at 2.76 pg/ml. Stratified analyses revealed positive correlations in specific subgroups, with interactions involving age, race, family income, recreational activity, and ln(sNfL). MR using IVW found no significant causal relationship between sNfL and depression genetically (OR = 0.956, 95 % CI: 0.878–1.042), with reverse analysis yielding similar results (OR = 0.897, 95 % CI: 0.756–1.065). ConclusionsThis cross-sectional study highlights a significant correlation between ln(sNfL) and depression. However, MR results indicate no causal relationship between sNfL and depression.

Potential mechanisms of gut microbiota influence on different types of vertigo: a bidirectional Mendelian randomization and mediation analysis

BackgroundThe relationship between gut microbiota and vertigo, specifically Benign Paroxysmal Vertigo (BPV) and Vertigo of Central (VC), remains underexplored.Aim and hypothesesThis study aims to investigate the causal relationships between gut microbiota and two types of vertigo, BPV and VC. Additionally, the study seeks to explore the mediation effects of metabolic, inflammatory, and psychological factors on these relationships. We hypothesize that specific taxa of gut microbiota have a causal effect on the risk of developing BPV and VC. The mediation effects of HbA1c, obesity, major depression, and interleukin-18 levels significantly influence the relationships between gut microbiota and vertigo.MethodUtilizing a bidirectional two-sample Mendelian randomization approach, this study investigated causal associations between gut microbiota and the two types of vertigo. A network MR assessed mediation effects of HbA1c, major depression, obesity, and interleukin-18 levels, with data sourced from several consortia, including MiBioGen.ResultsDistinct gut microbiota displayed varying influences on BPV and VC risks. A total of ten taxa affect BPV. Among these, two taxa have an odds ratio (OR) greater than 1, including one class, one order. Conversely, eight taxa have an OR less than 1, encompassing four families, three genera, and one order. The OR for these taxa ranges from 0.693 to 0.930, with p-values between 0.006 and 0.048. For VC, eight taxa were found to have an impact. Five of these taxa exhibit an OR greater than 1, including four genera and one phylum. The OR for these taxa ranges from 1.229 to 2.179, with p-values from 0.000 to 0.046. The remaining three taxa have an OR less than 1, comprising one family and two genera, with an OR range of 0.445 to 0.792 and p-values ranging from 0.013 to 0.050. The mediation analysis for BPV shows that major depression, obesity, and HbA1c are key mediators between specific taxa and BPV. Major depression mediates 28.77% of the effect of family Rhodospirillaceae on BPV. Obesity mediates 13.90% of the effect of class Lentisphaeria/order Victivallales. HbA1c mediates 11.79% of the effect of genus Bifidobacterium, 11.36% of family Bifidobacteriaceae/order Bifidobacteriales. For VC, interleukin-18 levels and major depression are significant mediators. Interleukin-18 levels mediate 6.56% of the effect of phylum Actinobacteria. Major depression mediates 6.51% of the effect of genus Alloprevotella.ConclusionThe study highlights potential causal links between gut microbiota and vertigo, emphasizing metabolic and psychological mediators. These insights underscore the therapeutic potential of targeting gut health in vertigo management.

Causal association between 731 immunocyte phenotypes and liver cirrhosis: A bidirectional two-sample mendelian randomization analysis.

Liver cirrhosis is a progressive hepatic disease whose immunological basis has attracted increasing attention. However, it remains unclear whether a concrete causal association exists between immunocyte phenotypes and liver cirrhosis. To explore the concrete causal relationships between immunocyte phenotypes and liver cirrhosis through a mendelian randomization (MR) study. Data on 731 immunocyte phenotypes were obtained from genome-wide association studies. Liver cirrhosis data were derived from the Finn Gen dataset, which included 214403 individuals of European ancestry. We used inverse variable weighting as the primary analysis method to assess the causal relationship. Sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. The MR analysis demonstrated that 11 immune cell phenotypes have a positive association with liver cirrhosis [P < 0.05, odds ratio (OR) > 1] and that 9 immunocyte phenotypes were negatively correlated with liver cirrhosis (P < 0.05, OR < 1). Liver cirrhosis was positively linked to 9 immune cell phenotypes (P < 0.05, OR > 1) and negatively linked to 10 immune cell phenotypes (P < 0.05; OR < 1). None of these associations showed heterogeneity or horizontally pleiotropy (P > 0.05). This bidirectional two-sample MR study demonstrated a concrete causal association between immunocyte phenotypes and liver cirrhosis. These findings offer new directions for the treatment of liver cirrhosis.

Association between blood mitochondrial DNA copy number and mental disorders: A bidirectional two-sample mendelian randomization study

BackgroundMitochondria is essential for cellular energy production, oxidative stress, and apoptosis. Mitochondrial DNA (mtDNA) encodes essential proteins for mitochondrial function. Although several studies have explored the association between changes in mtDNA copy number (mtDNA-CN) and risk of mental disorders, the results remain debated. This study used a bidirectional two-sample Mendelian randomization (MR) analysis to examine the genetic causality between mtDNA-CN and mental disorders. MethodsGenome-wide association study (GWAS) data for mtDNA-CN were sourced from UK biobank, involving 383,476 European cases. GWAS data for seven mental disorders—attention deficit/hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia, bipolar disorder, major depressive disorder, anxiety, and obsessive-compulsive disorder—were primarily obtained from the Psychiatric Genomics Consortium. Causal associations were assessed using inverse variance weighting, with sensitivity analyses via the weighted median and MR-Egger methods. Reverse MR considered the seven mental disorders as exposures. All analyses were replicated with additional mtDNA-CN GWAS data from 465,809 individuals in the Heart and Ageing Research in Genomic Epidemiology consortium and the UK Biobank. ResultsForward MR observed a 27 % decrease in the risk of ASD per standard deviation increase in genetically determined blood mtDNA-CN (OR = 0.73, 95%CI: 0.58–0.92, p = 0.002), with no causal effects on other disorders. Additionally, reverse MR did not indicate a causal association between any of the mental disorders and mtDNA-CN. Validation analyses corroborated these findings, indicating their robustness. ConclusionsOur study supports the potential causal association between mtDNA-CN and the risk of ASD, suggesting that mtDNA-CN could serve as a promising biomarker for early screening of ASD.

Vitamin D and Gestational Diabetes Mellitus in the IEU OpenGWAS Project: A Two-Sample Bidirectional Mendelian Randomization Study.

Gestational diabetes mellitus (GDM) is one of the most prevalent pregnancy problems, and there is still debate over the relationship between vitamin D and GDM. Our objective is to investigate the correlation between vitamin D and GDM by employing Mendelian randomization (MR) with summary data obtained from genome-wide association studies (GWAS). Data on exposures and outcomes, namely vitamin D, vitamin D insufficiency, and GDM, were acquired from the IEU OpenGWAS Project. Bidirectional MR analysis was performed utilizing the inverse variance weighted (IVW) method as the principal analytical approach. The complementary approaches employed in this study encompassed weighted median, simple mode, weighted mode, and MR-Egger regression. A series of sensitivity analysis were conducted in order to assess the reliability of the obtained results. The data were acquired from the IEU OpenGWAS Project. Following the application of the three assumptions of MR, 13 single nucleotide polymorphisms (SNPs) were included in the MR analysis for vitamin D levels and vitamin D deficiency on GDM, and 10 and 26 SNPs were included for GDM on vitamin D levels and deficiency, respectively. The findings from the IVW analysis revealed a significant positive correlation between vitamin D levels and GDM (OR = 1.057, 95% CI: 1.011-1.104, p = 0.015). Conversely, a negative correlation was seen between vitamin D deficiency and GDM (OR = 0.979, 95% CI: 0.959-0.999, p = 0.039). The results of the reverse MR study revealed no evidence of reverse causation between GDM and vitamin D. The findings from multiple MR approaches were in line with the direction of IVW analysis. Sensitivity analysis revealed no evidence of heterogeneity, pleiotropy, or outliers, suggesting the robustness of the results. There exists a causal association between vitamin D and GDM, whereby vitamin D levels serve as a risk factor for GDM.