Bidirectional Mendelian Randomization Research Articles

Causal association between metabolic syndrome and ovarian dysfunction: a bidirectional two-sample mendelian randomization

BackgroundThe relationship between Metabolic Syndrome (MetS) and ovarian dysfunction has been widely reported in observational studies, yet it remains not fully understood. This study employs genetic prediction methods and utilizes summary data from genome-wide association studies (GWAS) to investigate this causal link.MethodsWe employed a bidirectional two-sample Mendelian Randomization (MR) analysis utilizing MetS and ovarian dysfunction summary data from GWAS. Inverse variance weighted (IVW) was employed as the primary MR method, supplemented by Weighted Median, Weighted Mode, and MR-Egger methods. The robustness of the results was further assessed through sensitivity analyses including MR-Egger regression, MR-PRESSO, Cochran’s Q, and leave-one-out test.ResultsOur MR analysis identified a causal relationship between genetically determined insulin resistance (OR = 0.26, 95% CI: 0.08–0.89, P = 0.03), waist circumference (OR = 2.14, 95% CI: 1.45–3.15, P < 0.001), BMI (OR = 2.1, 95% CI: 1.56–2.83, P < 0.001) and ovarian dysfunction. Conversely, reverse MR analysis confirmed causal effects of ovarian dysfunction on metabolic syndrome (OR = 0.98, 95% CI: 0.97–0.99, P < 0.001) and waist circumference (OR = 0.99, 95% CI: 0.98–0.99, P = 0.02). The results of MR-Egger regression test indicated that the whole analysis was not affected by horizontal pleiotropy. Additionally, the MR-PRESSO test identified outliers in SNPs, but after removal of outliers, results remained unchanged.ConclusionThis study reveals a bidirectional causal connection between metabolic syndrome and ovarian dysfunction via genetic prediction methods. These findings are crucial for advancing our understanding of the interactions between these conditions and developing strategies for prevention and treatment.

Unraveling the Causal Relationship Between 731 Immunocyte Phenotypes and Asthma Risk: A Bidirectional Mendelian Randomization Analysis.

Growing evidence suggests an association between various immune cell phenotypes and the development of asthma. However, it is still not entirely clear whether specific immune cell phenotypes might causally contribute to the risk of asthma. Despite further studies required to validate this claim, our study delves deeper into explaining this relationship and paving the way toward new therapeutic approaches. Our initial aim is to reveal the causal relationship between 731 immunocyte phenotypes and asthma; a bidirectional Mendelian randomization (MR) analysis was performed. We have investigated 731 immunocyte phenotypes in asthma, using a summary of previously published GWAS. Conducting an MR analysis, we have interpreted the potential causative relationship between them. Our analytical approaches included inverse variance-weighted average, weighted median (WM) modeling, and pattern-based approaches. To ensure the robustness and accuracy of our findings, we conducted sensitivity analyses employing MR-PRESSO, Cochran's Q test, leave-one-out, and MR-Egger approaches. Additionally, we conducted a reverse MR analysis to examine potential reverse causality. Our study revealed 43 immunophenotypes with a causal connection to asthma risk. Following Bonferroni correction and sensitivity analysis, we have identified four immunophenotypes with strong causal associations and reliability, them being: HLA DR on DC (95% CI: 1.0008-1.0014, p = 4.26 × 10-6, FDR = 2.21 × 10-8), CD8 on CD28- CD8br (95% CI: 1.0007-1.0020, p = 4.01 × 10-5，FDR = 5.70 × 10-4), CD62L on monocyte (95% CI: 0.9985-0.9995，p = 1.06 × 10-4，FDR = 9.20 × 10-4), CD8br% leukocyte (95% CI: 1.0006-1.0019，p = 1.07 × 10-4，FDR = 1.14 × 10-3). We have confirmed the large co-inheritance of all these immunophenotypes, which suggests a contribution to asthma development. In addition, reverse MR confirmed that asthma and immune cell phenotypes lack a causal association between them. Our study provides evidence of different immune phenotypes, which are either beneficial or detrimental to asthma. Given the fact that asthma is a broad disease and contains complex immune mechanisms, this research may offer improved outcomes and long-term asthma treatment strategies.

Exploring the causal relationship between PAH and some autoimmune diseases using bidirectional Mendelian randomization analyses.

The causal association between pulmonary arterial hypertension (PAH) and autoimmune diseases remains uncertain. This study aimed to assess the causal associations between PAH and autoimmune diseases using bidirectional Mendelian randomization (MR) analyses. Genome-wide association summary statistics for PAH, asthma, myasthenia gravis, rheumatoid arthritis (RA), systemic lupus erythematosus, and type 1 diabetes mellitus were obtained from publicly accessible databases. The primary MR approach used was the inverse variance weighted method. Sensitivity analyses were conducted to test the robustness of the MR findings, including tests for heterogeneity, horizontal pleiotropy, and leave-one-out analysis, ensuring the reliability and validity of the results. Ultimately, transcriptome analysis was used for GO, KEGG enrichment analysis and protein interaction network. Bidirectional Mendelian randomization analysis found a causal relationship between PAH and RA (OR [95% CI] > 1; P < .05). Enrichment analysis further revealed the common molecular mechanisms of these 2 diseases, especially the dysfunction of chemokine pathway and other inflammation-related signaling pathways. Additionally, the study uncovered the core genes within the co-morbidity-associated protein-protein interaction network, including CCL5, CCL9, and VCAM1. Transcription factor (TF) network analysis showed that TFs such as GATA1, JUN and RELA were significantly up-regulated in PAH, and they play a key role in regulating cell proliferation and immune response. The study found a bidirectional positive causal link between PAH and RA. Dysregulation of the chemokine pathway and other inflammation-related signaling pathways may be momentous factors driving the progression of PAH and RA.

The association between benign and malignant prostatic hyperplastic diseases and blood and urine biomarkers: A Mendelian randomization study.

The identification of suitable biomarkers holds significant clinical importance for the early detection of benign prostatic hyperplasia (BPH) and prostate cancer (PCa). This study aimed to conduct a comprehensive analysis of the relationship between BPH and blood and urine biomarkers (BUB), as well as PCa and BUB. Candidate single nucleotide polymorphisms associated with BPH or PCa were derived from recent genome-wide association studies. The UK Biobank cohort comprised 363,228 individuals with BUB test data, enabling the calculation of a polygenic risk score for BPH or PCa. Bidirectional 2-sample Mendelian randomization was employed to assess the potential causal association between candidate BUB and BPH, as well as between BUB and PCa. In this study, a notable correlation was observed between BPH and gamma-glutamyl transferase (r = 1.061658447, P = .028697428). PCa exhibited significant associations with insulin-like growth factor 1 (r = 1.119051258, P = .004101067), Lipoprotein A (r = 1.120348291, P = .038093372), total protein (r = 0.87643517, P = .01657563), and non-albumin protein (r = 0.905333153, P = .03103913). The findings offer valuable insights into the significance of BUB in the timely identification and management of BPH and PCa.

Cathepsins and their role in gynecological cancers: Evidence from two-sample Mendelian randomization analysis.

Prior studies have reported connections between cathepsins (CTS) and gynecological cancers; however, the exact causal links are yet to be fully understood. Leveraging publicly accessible genome-wide association study summary datasets, we performed a two-sample bidirectional Mendelian randomization (MR) and multivariate MR (MVMR) analysis, with the inverse variance weighted (IVW) method as the primary approach. MR analysis demonstrated inverse associations between CTSB and cervical cancer (IVW: odds ratio [OR] = 0.9995, 95% confidence interval [CI] = 0.9991-0.9999, P = .0418), CTSE and ovarian cancer (IVW: OR = 0.9197, 95% CI = 0.8505-0.9944, P = .0358), CTSZ and ovarian cancer (IVW: OR = 0.9449, 95% CI = 0.8938-0.9990, P = .0459), CTSE and high grade serous ovarian cancer (IVW: OR = 0.8939, 95% CI = 0.8248-0.9689, P = .0063), and CTSZ and high grade serous ovarian cancer (IVW: OR = 0.9269, 95% CI = 0.8667-0.9913, P = .0268). A positive correlation was identified between CTSH and clear cell ovarian cancer (IVW: OR = 1.1496, 95% CI = 1.0368-1.2745, P = .0081). Nevertheless, subsequent adjustment for the false discovery rate revealed that none of the P-values retained statistical significance (PFDR > 0.05). MVMR analysis results elucidated that CTSZ was inversely associated with cervical cancer (IVW: OR = 0.9988, 95% CI = 0.9981-0.9996, P = .0022). Moreover, a positive association was noted between CTSF and cervical cancer (IVW: OR = 1.0007, 95% CI = 1.0000-1.0014, P = .0364), and similarly, between CTSS and cervical cancer (IVW: OR = 1.0005, 95% CI = 1.0000-1.0011, P = .0490). CTSO exhibited a positive association with non-endometrioid endometrial cancer (IVW: OR = 1.4405, 95% CI = 1.1864-1.7490, P < .001), and CTSH was positively associated with clear cell ovarian cancer (IVW: OR = 1.1167, 95% CI = 1.0131-1.2310, P = .0263). The MVMR analysis findings reveal that CTSZ emerges as a protective element against cervical cancer, whereas CTSF and CTSS represent risk factors for this disease. CTSO stands out as a risk factor for non-endometrioid endometrial cancer, and CTSH acts as a risk factor for clear cell ovarian cancer. This study elucidates causative connections between CTS and gynecological cancers, providing innovative insights for diagnostic and therapeutic optimization.

Causal associations of frailty and type 2 diabetes mellitus: A bidirectional Mendelian randomization study.

Type 2 diabetes mellitus (T2DM) is a common metabolic disease that can lead to a wide range of complications and impose a significant economic burden to society. Frailty is a disease associated with the accumulation of health deficits that may affect the quality of life of T2DM patients. This Mendelian randomization (MR) study explores the bidirectional causality between T2DM and frailty. All the data was available online at the IEU OpenGWAS project for this study, with the original data for T2DM coming from the pooled statistics of 468,298 participants in the UK biobank, and for frailty from the pooled summary statistics of a total of 175,226 participants in the UK biobank and Swedish TwinGene. The populations were all of European ancestry. Inverse variance weighting (IVW) was the main analytical method for assessing the causal effects of exposure and outcome, in addition, we also complemented weighted median and MR-Egger methods. Heterogeneity tests were performed with Cochran Q statistic and I2 statistic, and horizontal pleiotropy tests were detected through an intercept term in the MR-Egger regression model and MR-PRESSO. A sensitivity analysis was further performed with the leave-one-out method to estimate the impact of individual genetic variants on the overall outcomes. At the gene level, we identified 63 single nucleotide polymorphisms (SNPs) associated with T2DM and 14 SNPs associated with frailty for MR analysis. In the bidirectional MR analysis, the MR-Egger intercept and MR-PRESSO revealed no horizontal pleiotropy (P > .05), while significant heterogeneities were found by the heterogeneity test (P < .05). IVW results showed that frailty significantly increased the risk of T2DM (OR = 2.33, 95% confidence interval [CI] = 1.66-3.26, P < .001), and the similar result existed in the reverse MR analysis (OR = 1.04, 95% CI = 1.02-1.06, P < .001). A bidirectional causal relationship exists between T2DM and frailty, with intervention for either disease reducing the risk of the other.

Investigating the controversy surrounding statin therapy and Achilles tendinopathy using Mendelian randomization analysis.

The relationship between statin therapy and tendon injuries, particularly Achilles tendinopathy, which is the body's largest and strongest tendon, remains controversial. This study employed Mendelian Randomization (MR) analysis to explore the causal link between statin therapy and Achilles tendinopathy (ATP). Summary statistics were obtained from genome-wide association studies on statin medication and four specific statin drugs from public databases, as well as data related to two ATP phenotypes, namely Achilles tendinitis and Achilles tendon injury. Furthermore, a two-sample bidirectional MR analysis was conducted to investigate the association between statin therapy and ATP. The primary method used was the inverse variance weighted (IVW) method, supplemented by four other validation methods. Heterogeneity analysis, pleiotropy assessment, and leave-one-out sensitivity analysis were further conducted to validate the robustness of the results. Based on our comprehensive investigation, all MR analyses in this study found no significant causal relationship between statin therapy and ATP (IVW, p > 0.05). Notably, the MR findings regarding pravastatin, rosuvastatin, and ATP were limited by a small pool of instrumental variables, necessitating further research. Moreover, no association was observed between the two in the reverse MR analysis (IVW, p > 0.05). All results passed heterogeneity tests, pleiotropy tests, and sensitivity analyses. Our results do not establish a causal connection between statin therapy and ATP, indicating that individuals with ATP should consider alternative pathogenic contributors. Moreover, these findings highlight the safety profile of statin medications.

Exploring the silent connection: unveiling the intricate relationship between gastroesophageal reflux disease and sleep apnea syndrome

BackgroundGastroesophageal reflux disease (GERD) and Sleep Apnea Syndrome (SAS) are two prevalent medical conditions that significantly affect health and quality of life. GERD involves stomach content reflux into the esophagus, while SAS causes recurrent upper airway obstruction during sleep. Despite recent studies hinting at a link, the precise relationship and causality between GERD and SAS remain unclear. Our research uses bidirectional Mendelian randomization to explore this intricate relationship. Additionally, given SAS's high prevalence in cardiovascular patients (40–80%, as highlighted by the American Heart Association), we also investigated its potential association with various cardiovascular diseases to gain new insights into prevention and treatment.MethodsThis study employed genetic data from large-scale genome-wide association studies (GWAS) on GERD (129,080 cases, 473,524 controls) and SAS (25,008 cases, 391,473 controls) for two-sample Mendelian randomization (MR) analysis to estimate the causal effects of GERD on the risk of SAS. All SNPs were selected using a strict clump window (r2 = 0.001 and kb = 10,000). We initially applied the inverse variance weighted (IVW) method and measured horizontal pleiotropy using MR-Egger, weighted median, and weighted mode methods. I2 index and Cochran Q statistics were used for sensitivity analysis. Funnel plot symmetry of IVW MR estimates versus 1/standard error (1/SEIV) was examined to exclude SNPs potentially causing heterogeneity. Additionally, to exclude reverse causality, bidirectional MR was employed to investigate whether genetic susceptibility to SAS causally influenced the risk of GERD.ResultsGERD was associated with an elevated risk of SAS, demonstrating an odds ratio (OR) of 1.750 (95% CI 1.590–1.930; P < 0.001). Conversely, there was no compelling evidence to indicate a causal link between SAS and the risk of developing GERD, with an OR of 1.000 (95% CI 0.989–1.011; P = 0.964). In addition to the primary findings, our study also revealed significant risks associated with SAS for several cardiovascular conditions, including coronary heart disease, atrial fibrillation, coronary artery disease, heart failure, intracerebral hemorrhage, and ischemic stroke.ConclusionWe discovered compelling evidence indicating an elevated risk of SAS in individuals with GERD, but no significant evidence supporting an increased risk of GERD in those with SAS. Future investigations into SAS risk should take into account the potential therapeutic targeting of GERD. PPI and histamine antagonists can effectively reduce reflux and airway secretions, preventing airway damage and collapse. Furthermore, it is necessary to investigate the underlying mechanisms by which GERD affects SAS. For example, the inflammatory stimulation caused by gastric acid and pepsin in refluxed fluid, as well as the increased tension of bronchial smooth muscle caused by vagus nerve reflex. Thus, early preventive measures can be implemented for potential complications related to SAS.

Exploring the causal relationship between serum EFNB2 levels and epilepsy: a bidirectional Mendelian randomization and co-localization analysis

Exploring the causal relationship between serum EFNB2 levels and epilepsy: a bidirectional Mendelian randomization and co-localization analysis

The causal effect of glaucoma and diabetic retinopathy: a Mendelian randomization study

BackgroundPrevious research showed that there is an important association between glaucoma and diabetic retinopathy (DR). However, the relationship has not been clarified. In this study, we attempted to evaluate it.MethodsWe conducted bidirectional Two-sample Mendelian randomization (MR), Multivariable Mendelian randomization (MVMR), and Mediation analysis. The Inverse-variance-weighted method was adopted as the main MR method, supplemented by MR-Egger, weighted median, weighted mode, and simple mode.ResultsThe results of forward MR analysis suggested that glaucoma [p = 0.001, odds ratio (OR) = 1.080] and intraocular pressure (IOP) (p = 0.019, OR = 1.100) as risk factors for DR. The reverse MR found that DR was a risk factor for glaucoma (p = 0.039, OR = 1.024) and IOP (p = 0.010, OR = 1.057). The results of MVMR analysis demonstrated that glaucoma (p = 0.046, OR = 1.069) remained an independent risk factor for DR. The bidirectional relationship between glaucoma and DR is mediated by IOP, according to the results of the Two-step MR analysis. Besides, glaucoma contributed to the positive causal link that exists between IOP and DR.ConclusionThe findings demonstrated a reciprocal causal link between glaucoma and DR, with a possible mediating function for IOP. Moreover, glaucoma played an important mediator of IOP as a risk factor for DR. It offers recommendations for the early prevention of both DR and glaucoma.

Evidence for Genetic Causal Association Between the Gut Microbiome, Derived Metabolites, and Age-Related Macular Degeneration: A Mediation Mendelian Randomization Analysis

Background/Objectives: Despite substantial research, the causal relationships between gut microbiota (GM) and age-related macular degeneration (AMD) remain unclear. We aimed to explore these causal associations using Mendelian randomization (MR) and elucidate the potential mechanisms mediated by blood metabolites. Methods: We utilized the 211 GM dataset (n = 18,340) provided by the MiBioGen consortium. AMD outcome data were sourced from the MRC Integrated Epidemiology Unit (IEU) OpenGWAS Project. We performed bidirectional MR, two mediation analyses, and two-step MR to assess the causal links between GM and different stages of AMD (early, dry, and wet). Results: Our findings indicate that the Bacteroidales S24.7 group and genus Dorea are associated with an increased risk of early AMD, while Ruminococcaceae UCG011 and Parasutterella are linked to a higher risk of dry AMD. Conversely, Lachnospiraceae UCG004 and Anaerotruncus are protective against dry AMD. In the case of wet AMD, Intestinimonas and Sellimonas increase risk, whereas Anaerotruncus and Rikenellaceae RC9 reduce it. Additionally, various blood metabolites were implicated: valine, arabinose, creatine, lysine, alanine, and apolipoprotein A1 were associated with early AMD; glutamine and hyodeoxycholate—with a reduced risk of dry AMD; and androsterone sulfate, epiandrosterone sulfate, and lipopolysaccharide—with a reduced risk of wet AMD. Notably, the association between family Oxalobacteraceae and early AMD was mediated by valine, accounting for 19.1% of the association. Conclusions: This study establishes causal links between specific gut microbiota and AMD, mediated by blood metabolites, thereby enhancing our understanding of the gut–retina axis in AMD pathophysiology.

Assessment of the causal association between obstructive sleep apnea and telomere length: a bidirectional mendelian randomization study

BackgroundA plethora of observational studies has established a significant correlation between Obstructive Sleep Apnea (OSA) and Telomere Length (TL). Nevertheless, a universal consensus on precise causal association and its directionality has not yet been achieved. To shed light on this, we employed Mendelian Randomization (MR) to investigate the bidirectional causal association between OSA and TL.MethodUtilizing publicly accessible Genome-Wide Association Studies (GWAS) datasets, we procured genetic data pertinent to MR analysis. The study incorporated samples from both the OSA (n = 217,955) and TL (n = 472,174) cohorts. In the forward MR analysis, OSA served as the exposure variable and TL as the outcome. Conversely, the reverse MR analysis treated TL as the exposure and OSA as the outcome. We employed the Inverse variance weighted (IVW) as the primary methodology for MR analysis. To ensure the robustness of our MR findings, multiple sensitivity analyses were performed.ResultsIn the forward MR analysis, a negative correlation was indicated between OSA and TL (IVW: odds ratio (OR) = 0.964, 95% confidence interval (CI): 0.939–0.980, P = 0.006 &amp;lt; 0.05). However, no significant association was identified between TL and the risk of OSA in the reverse MR analysis (IVW: OR = 0.965, 95% CI: 0.870–1.070, P = 0.499 &amp;gt; 0.05).ConclusionOur study indicated a potential association between OSA and the increased risk of shorter TL, offering vital academic support for future clinical studies on this association.

Exploration of the causal relationship and mechanisms between serum albumin and venous thrombosis: a bidirectional mendelian randomization analysis and bioinformatics study

BackgroundTo explore the causal relationship between serum albumin and venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and its consequential condition, pulmonary embolism (PE), through Mendelian randomization (MR) design, seeking to clarify the protective roles of albumin in the development of venous thrombosis.MethodsWe performed a bidirectional two-sample Mendelian randomization analysis utilizing albumin genome-wide association study (GWAS) data alongside VTE datasets from various sources. Additionally, to minimize heterogeneity across different datasets, a meta-analysis of the Mendelian randomization results was conducted. Furthermore, genes associated with such exposures were identified to unravel how exposure impacts outcomes. This was followed by applying bioinformatics techniques for gene enrichment analysis and employing the Cytoscape software to pinpoint the hub genes.ResultsThe findings from the meta-analysis of the Mendelian randomization indicate that reduced levels of albumin are associated with an elevated risk of VTE (OR = 0.739, 95% CI: 0.695 to 0.787, P = 1.82e-9), DVT (OR = 0.700, 95% CI: 0.646 to 0.772, P = 2.96e-15), and PE (OR = 0.717, 95% CI: 0.647 to 0.793, P = 1.74e-10). Bioinformatics analysis revealed that serum albumin primarily protects against VTE by influencing inflammation and cytokines.ConclusionsOur bidirectional MR analysis confirmed a substantial causal association linking serum albumin to VTE. Bioinformatics analysis revealed that this causal link is mediated by the immune response through inflammation and cytokines.

Causal relationship between immune cell signatures and colorectal cancer: a bi-directional, two-sample mendelian randomization study

BackgroundPrior studies have demonstrated the association between immune cells and colorectal cancer (CRC). However, the causal link to specific immunophenotypes is limited. This study intends to elucidate the causal relationship of immune cell signatures on CRC.MethodsWe performed a bi-directional and two-sample mendelian randomization (MR) study, utilizing GWAS summary data of 731 immune cell traits (n = 3,757) and CRC statistics (n = 470,002). The primary MR methodology was inverse-variance weighted (IVW) method. Furthermore, heterogeneity was evaluated by Cochran’s Q test. MR-PRESSO and MR-Egger were employed to assess horizontal and vertical pleiotropy respectively. Sensitivity analysis and FDR correction were conducted in our results. These results were validated in both the UK Biobank and FinnGen cohorts. We also extracted transcriptomic data of CRC and adjacent non-tumor tissues from TCGA, and used CIBERSORT to compare the infiltration patterns of 22 immune cell panels between normal tissues and the tumor microenvironment (TME).ResultsOur study indicated nine immune cell signatures had significant causality with the risk of CRC after sensitivity analysis and FDR correction. The positive results covered four panels: B cell, CD8 + T cell, Treg, and monocyte. IgD- CD38br and IgD + CD38br B cell, CD8dim and CD28 + CD45RA- CD8dim T cell, and CD14 on CD14 + CD16- monocyte were the protective factors of CRC. However, CD39 + resting Treg, CX3CR1 on CD14- CD16 + monocyte, FSC-A on HLA DR + T cell, and BAFF-R on B cell increased the risk of CRC. The results were validated in the UK Biobank data and FinnGen cohorts. The data from the TCGA database also confirmed the infiltration of B cell, CD8 + T cell, Treg, and monocyte panels in the TME.ConclusionThis study highlights the causal link between specific immune cell phenotypes and CRC, providing valuable insights into the immune microenvironment’s role in CRC. The validation of our findings using large-scale datasets (UK Biobank, FinnGen) and TCGA underscores the robustness of our results, offering new potential therapeutic targets for CRC treatment.

Bidirectional Mendelian randomization study reveals interplay between multisite chronic pain and Post-traumatic stress disorder

To determine the causal relationship between multisite chronic pain (MCP) and post-traumatic stress disorder (PTSD) using Mendelian Randomization (MR) analysis. Genome-wide summary statistics for MCP and PTSD were obtained. Linkage disequilibrium score regression (LDSC) analysis was used to assess genetic correlation. Independent SNPs associated with MCP and PTSD were used as instrumental variables for forward and reverse MR analyses. The inverse variance weighted (IVW) method was the primary analysis, with additional sensitivity tests to ensure robustness. LDSC identified a significant genetic correlation between MCP and PTSD (rg = 0.635, P = 1.40E-110). The forward MR analysis indicated a positive causal association between the number of MCP sites and the PTSD risk (Odds Ratio [OR] = 1.103, 95% CI: 1.026–1.186, P = 7.89E-03). Conversely, the reverse MR analysis showed that PTSD significantly increased the number of MCP sites (β = 0.244, 95% CI: 0.143–0.345, P = 2.08E-06). Sensitivity tests suggested the robustness of the MR estimation, indicating no significant heterogeneity or horizontal pleiotropy. A bidirectional positive causal relationship between MCP and PTSD was identified, highlighting the need for integrated treatment and preventive strategies that address both conditions simultaneously to improve health outcomes.

Unraveling the role of proteins in dementia: insights from two UK cohorts with causal evidence

Abstract Population-based proteomics offers a groundbreaking avenue to predict future disease risks, enhance our understanding of disease mechanisms, and discover novel therapeutic targets and biomarkers. The role of plasma proteins in dementia, however, requires further exploration. This study investigated 276 protein-dementia associations in 229 incident all-cause dementia, 89 Alzheimer’s disease, and 41 vascular dementia among 3,249 participants (55% women, 97.2% white ethnicity) from the English Longitudinal Study of Ageing (ELSA) over a median 9.8-year follow-up. We used Cox proportional hazard regression for the analysis. Receiver operating characteristic analyses were conducted to assess the precision of the identified proteins from the fully adjusted Cox regression models in predicting incident all-cause dementia, both individually and in combination with demographic predictors, APOE genotype, and memory score, to estimate the area under the curve. Additionally, the eXtreme Gradient Boosting machine learning algorithm was used to identify the most important features predictive of future all-cause dementia onset. These associations were then validated in 1,506 incident all-cause dementia, 732 Alzheimer’s disease, 281 vascular dementia, and 111 frontotemporal dementia cases among 52,745 individuals (53.9% women, 93.3% white ethnicity) from the UK Biobank over a median 13.7-year follow-up. Two-sample bi-directional Mendelian randomization and drug target Mendelian randomization were further employed to determine the causal direction between protein concentration and dementia. NEFL (Hazard ratio [HR] [95% confidence intervals (CI)]: 1.54 [1.29, 1.84]) and RPS6KB1 (HR [95% CI]: 1.33 [1.16, 1.52]) were robustly associated with incident all-cause dementia; MMP12 (HR [95% CI]: 2.06 [1.41, 2.99]) was associated with vascular dementia in ELSA, after correcting for multiple testing. Additional markers EDA2R and KIM1 were identified from subgroup and sensitivity analyses. Combining NEFL and RPS6KB1 with other predictors yielded high predictive accuracy (area under the curve=0.871) for incident all-cause dementia. The eXtreme Gradient Boosting machine learning algorithm also identified RPS6KB1, NEFL, and KIM1 as the most important protein features for predicting future all-cause dementia. Sex difference was evident for the association between RPS6KB1 and all-cause dementia, with stronger association in men (p for interaction=0.037). Replication in the UK Biobank confirmed the associations between the identified proteins and various dementia subtypes. The results from Mendelian randomization in the reverse direction indicated that several proteins serve as early markers for dementia, rather than being direct causes of the disease. These findings provide insights into putative mechanisms for dementia. Future studies are needed to validate the findings on RPS6KB1 in relation to dementia risk.

Genetic Evidence Indicates that Serum Micronutrient Levels Mediate the Causal Relationships Between Immune Cells and Neuropathic Pain: A Mediation Mendelian Randomization Study.

A growing body of evidence suggests a correlation among immune cells, serum micronutrient levels, and neuropathic pain. However, previous studies have been limited in scope, hindering the establishment of conclusive findings. Therefore, this study employs mendelian randomization (MR) analysis to investigate the genetic perspectives on the causal relationships among these factors. Initially, the relationship between five serum micronutrient levels (specifically, four vitamin levels and zinc levels) and neuropathic pain was examined using a bidirectional MR design. Subsequently, positive results identified through the inverse variance weighted (IVW) method prompted further analysis, using immune cells as exposures to explore their causal links with neuropathic pain. As a result, a two-step MR analysis demonstrated that serum vitamin levels mediate the relationship between immune cells and neuropathic pain, quantifying both direct impacts and mediation effects. This study revealed that low serum levels of vitamin D and 25-hydroxyvitamin D increased the risk of postherpetic neuralgia and thoracic spine pain. Reverse MR analysis suggested that neuropathic pain does not contribute to a reduction in the serum levels of vitamin D and 25-hydroxyvitamin D. Furthermore, significant associations were observed between 27 immune cells and postherpetic neuralgia, as well as between 22 immune cells and thoracic spine pain. Additionally, the mediation analysis identified causal relationships between immune cells and serum micronutrient levels, confirming the "immune cells-serum micronutrient levels-neuropathic pain" pathway. This study provides valuable insights into the potential mechanisms by which vitamin D and 25-hydroxyvitamin D regulate the interaction between the immune system and neuropathic pain. These findings are crucial for the timely detection, treatment, and management of neuropathic pain, offering new perspectives on how vitamin levels influence immune cell behavior and neuropathic pain susceptibility.

Obstructive sleep apnea's causal links to depression, well-being, and negative moods: a bidirectional mendelian randomized study.

Previous observational studies showed associations between obstructive sleep apnea (OSA) and depression and other negative moods. However, the causality has not been determined. Single nucleotide polymorphisms were identified as instrumental variables by screening from genome-wide association studies. Bidirectional two-sample mendelian randomization (MR) was applied to assess the potential causal relationship between OSA and depression, subjective well-being, negative moods. Inverse variance weighting (IVW) method and weight median were chosen as the main methods to estimate possible causal effects. MR-Egger, MR pleiotropy residual sum and outlier and leave-one-out analysis methods, were used as sensitivity analysis methods to ensure robust results. MR analyses indicated significantly causal association of OSA on depression (OR = 1.22, P = .010) and major depressive disorder (OR = 1.02, P = .006). Furthermore, genetically predicted OSA was negatively associated with subjective well-being (βIVW = -0.06, P = .009), and was positively associated with negative moods including depressed affect (OR = 1.04, P = .012), irritable mood (P = .006), feeling lonely (P = .011), feeling fed-up (P = .005) and mood swings (P = .017). There is no reverse effect of the above psychiatric traits on OSA. Genetic predisposition to OSA causally increased depression and major depressive disorder. Consistently, OSA has causal impacts on both subjective well-being, representing positive emotions, and negative moods.

Investigating the causal relationship between skin microbiota and hypertrophic scar using bidirectional mendelian randomization.

Investigating the causal relationship between skin microbiota and hypertrophic scar using bidirectional mendelian randomization.

Causal relationship between gut microbiota, lipids, and neuropsychiatric disorders: A Mendelian randomization mediation study.

Causal relationship between gut microbiota, lipids, and neuropsychiatric disorders: A Mendelian randomization mediation study.