Potential Causal Relationship Research Articles

Association of serum testosterone levels with left atrial size, function, and risk of atrial fibrillation in adult men: observational and mendelian randomization analyses

Abstract Background Numerous studies have investigated the association between serum testosterone levels, testosterone replacement therapy (TRT), and cardiovascular risk. However, research examining the relationship between testosterone levels and atrial fibrillation (AF) risk remains limited. We comprehensively analyzed the association between total testosterone (TT) levels, intermediary phenotypes such as left atrium (LA) size and function, and the risk of AF in middle-aged and older men. Methods We utilized data from the UK Biobank, a population-based prospective cohort, focusing on 179,988 White men who had complete serum TT level data and no AF history. Observational associations between TT levels and LA imaging traits, as well as AF risk, were estimated using multivariable regression and time-dependent Cox regression models, treating TT levels as a time-varying variable. Genetic associations were examined by Mendelian randomization (MR), using both UK Biobank and external large consortia genome-wide association study data. Results During the median follow-up of 11.8 years (IQR 10.9–12.5), we observed 13,847 incident AF cases (7.7%). Participants with normal TT levels (≥ 300 ng/dL) showed a 15% reduced risk of AF (HR of 0.85 [95% CI, 0.82–0.89]) compared to those with low TT (< 300 ng/dL). Interestingly, participants undergoing TRT experienced a 51% higher risk of AF (1.51 [1.09–2.07]). Furthermore, each 1-standard deviation increase in TT levels was associated with a reduced AF risk (OR of 0.91 [0.89–0.93]) and an improved LA emptying fraction (1.29 [1.06–1.58]). Applying age-specific cutoff values for low TT levels highlighted a more pronounced AF risk reduction in participants with normal TT. MR analyses supported these observations, suggesting potential causal relationships between TT levels and both LA function and AF risk. Conclusions Our findings suggest that low TT levels are associated with reduced LA function and increased risk of AF, both observationally and genetically, indicating that serum TT could serve as a surrogate marker or even a potential causal mediator in the development of AF.Abstract tableAbstract figure

Does PhenoAge acceleration impact adverse outcomes following major surgery (rehospitalization or death)? A genome-wide association study and mendelian randomisation

Abstract Background Biological aging reflects the state of an individual's cellular and molecular function, and is distinct from chronological age; which reflects the passage of time[1]. Validated measures of biological aging, such as Phenotypic aging (PhenoAge) estimated from nine routine clinical biomarkers, have been associated with increased risk of age-related diseases and mortality in cohort studies[2]. However, the potential causal relationship between them remains unclear. In this study, we aim to identify genetic variants associated with PhenoAge Acceleration (PhenoAgeAccl) and adverse outcome after surgery (rehospitalisation or death within 365-days] and assess the causal relationship between these two phenotypes using Mendelian Randomization framework. Objectives -Perform a genome-wide association study(GWAS) on adverse outcomes following major surgery. -Assess the potential causal relationship between PhenoAgeAccl and adverse outcomes following major surgery using Mendelian randomization analysis. Methods We conducted a GWAS via plink using participants from the UKBiobank (Application 77596) to generate summary statistics for 6509 participants who had undergone major surgery within 365 days of their baseline assessment date(3). For quality control, SNPs were excluded if they didn't meet the following criteria: (1) imputation information score <0.3 (2) minor allele frequency <1%, (3) Hardy–Weinberg equilibrium test p-value significant at the Bonferroni-corrected level. Summary statistics for PhenoAgeAccl was obtained from a previous GWAS of European descents[4]. Gene enrichment analysis was performed using Multi-marker Analysis of GenoMic Annotation (MAGMA) in Functional Mapping and Annotation (FUMA). Then, genetic instruments for PhenoAgeAccl and adverse outcomes following surgery were identified to conduct a summary-based Mendelian Randomisation [Assumptions are listed in Figure 1]. Results GWAS for adverse outcomes following major surgery identified 3 lead SNPs (rs1360618, rs11848297, rs7978) [Figure 2]. Gene-set analysis showed enrichment in the immune system, cell migration, fear response, and iron metabolism. For PhenoAge Acceleration, gene-set analysis showed enrichment in immune system, and cell signalling pathways. 17 SNPs were selected which were used for the Two-Sample MR. We found no causal relationship, as the beta coefficient for Inverse variance weighted was -0.308 [standard error - 0.075, p=0.68]. For every 5-year increase in PhenoAge compared to chronological age, the risk of emergency re-hospitalisation or death increased by 21% (HR 1.16 – 1.3, p < 0.001). Conclusion Gene-set analysis for adverse outcomes following major surgery showed enrichment in immune system, iron metabolism, and fear response which have all recently been associated with mortality post-surgery in cohort studies(4,5). No causal relationship between PhenoAgeAccel and mortality post-surgery was established.Mendelian Randomisation assumptionsManhattan plot adverse-outcomes post-sur

Sleep Disturbances and Heart Failure: Observational Study and Mendelian Randomization Study

IntroductionSleep disturbances are prevalent among patients with heart failure (HF) and may trigger acute exacerbations of the condition. However, the causal relationship between sleep disturbances and HF remains uncertain. This study aims to explore the association and potential causal relationship between sleep disturbances and HF.Material and methodsObservational Study: NHANES data (2005-2008) involving 10,432 participants. Sleep disturbances defined as insomnia, sleep disorders, difficulty falling asleep, trouble sleeping, and waking up during the night. Mendelian randomization (MR) Study: Genetic variants linked to sleeplessness were obtained from GWAS datasets. MR Two-sample analysis was conducted using summary statistics from sleeplessness and HF GWASs.ResultsAfter full adjustment, the association between insomnia and HF remained significant, with an OR of 5.10 (1.81–14.33, P = 0.003). After full adjustment, the association between sleep disorder and HF remained significant, with an OR of 3.51 (1.67–7.39; P = 0.002). The IVW method provided evidence supporting a causal association between sleeplessness and HF (OR = 1.535, SE = 0.177, P = 0.016).MR-Egger analysis demonstrated a causal association between sleeplessness and HF (OR = 3.333, SE = 0.493, p =0.023). Our observational study may be influenced by unaddressed confounding factors; however, Mendelian randomization helps mitigate the bias and confounding commonly found in non-genetic observational research.ConclusionsOur study identified a correlation between sleep disturbances and HF, potentially suggesting a causal relationship. Addressing sleep disturbances may be a key strategy in reducing the risk of HF.

No bidirectional relationship between constipation and colorectal cancer in European and Asian populations: A Mendelian randomization study.

Traditional observational studies have reported a positive association between constipation and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between constipation and CRC is scarce. In the study, 2-sample Mendelian randomization analysis was conducted to investigate the potential causal relationship between constipation and CRC. Analysis of the results showed that there was no causal association between constipation and CRC, either in European populations (CRC: odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.99-1.00, P = .49; rectal cancer: OR = 0.99, 95% CI = 0.99-1.00, P = .79) or in Asian populations (CRC: OR = 1.00, 95% CI = 0.99-1.01, P = .30). Also there was no inverse causal association between CRC and constipation, either in European populations (CRC: OR = 0.10, 95% CI = 2.76E-03-3.45, P = .20; rectal cancer: OR = 0.05, 95% CI = 9.14E-07-2.64E + 03, P = .59) or in Asian population (CRC: OR = 1.18, 95% CI = 0.92-1.52, P = .20), there was no horizontal diversity in the instrumental variables in the Mendelian randomization analyses of the present study (all F statistics >10), and no heterogeneity was found in the regression analyses. The findings from bidirectional 2-sample Mendelian randomization analyses indicate that there is no evidence of a bidirectional causal association between constipation and CRC. However, further investigation is warranted through additional clinical studies and trials to thoroughly explore the association between these 2 factors.

Identification of JAZF1, KNOP1, and PLEKHA1 as causally associated genes and drug targets for Alzheimer's disease: a summary data-based Mendelian randomization study.

There is a growing body of evidence indicating the significant role of the immune system and immune cells in the progression of Alzheimer's disease (AD). However, the exact role of genes from various immune cell types in AD remains unclear. We aimed to utilize summary data-based Mendelian randomization (SMR) to explore the potential causal relationships between genes in specific immune cells and the risk of AD. By utilizing data sets of expression quantitative trait loci (eQTL) for 14 different immune cell types and large-scale AD genome-wide association study (GWAS), we employed SMR to identify key genes associated with AD within specific immune cells. Sensitivity analyses, including F-statistic, colocalization, and assessment of horizontal pleiotropy, were further conducted to validate the discovered genes. In addition, replication analyses were performed in AD GWAS from the FinnGen consortium. Finally, we further identified existing drugs that target or interact with the druggable genes and reviewed the studies about the associations between these drugs and AD. SMR analysis revealed 342 genes associated with AD across 14 immune cell types. Further sensitivity analyses identified nine genes, CTSH, FCER1G, FNBP4, HLA-E, JAZF1, KNOP1, PLEKHA1, RP11-960L18.1, and ZNF638 that had significant associations with AD across nine specific immune cell types. JAZF1, KNOP1 and PLEKHA1 were replicated in an independent analysis usingthe GWAS data. The review on gene-related drugs also supported these findings. Our research suggests that the expression of the genes JAZF1, KNOP1, and PLEKHA1 in specific immune cell types is related to the risk of AD.

Exploring the potential link between gut microbiota and chronic kidney disease in causality: A 2-sample Mendelian randomization study.

Increasing evidence indicates a significant correlation between gut microbiota (GM) and susceptibility to chronic kidney disease (CKD). However, causal relationship presence remains uncertain. Mendelian randomization (MR) was applied to evaluate potential causal relation from GM to CKD. Genomic association analysis aggregates publicly online databases, utilizing Genome-Wide Association Study (GWAS) database focused on GM and CKD. For examination of potential causal connection from GM to CKD, a 2-way, 2-sample Mendelian randomization (MR) method was applied. Sensitivity analyses were utilized to scrutinize for heterogeneity, horizontal pleiotropy, MR outcomes resilience. Result from inverse variance weighting (IVW) method revealed that 10 microbiotas such as Porphyromonadaceae (OR = 1.351, 95% CI: 1.114-1.638, P = .002), Dorea (OR = 1.236, 95% CI: 1.040-1.468, P = .016), Ruminococcus torques group (OR = 1.290, 95% CI: 1.035-1.608, P = .024) are potential CKD risk factors. Five microbiotas, including the Prevotellaceae (OR = 0.814, 95% CI: 0.719-0.922, P = .001) are potential CKD protective factors. Sensitivity analyses reveal no horizontal pleiotropy or heterogeneity. Additionally, reverse MR results unveiled potential relation between CKD and disorders in 3 microbiotas, including Senegalimassilia. According to the investigation, MR method was employed to delve into reciprocal causal connection from GM to CKD. Our findings identified 15 types of GM causally linked to CKD, as well as CKD demonstrating causal associations with 3 types of GM. Further exploration of these associated GM types is hopeful to raise novel insights, for CKD preventing and early monitoring.

Causal relationship between circulating inflammatory proteins and risk of different types of encephalitis: A two-sample Mendelian randomization study

BackgroundCytokines are potent molecules of the immune response. They act at the site of inflammation and circulate in the bloodstream. However, there are few studies on encephalitis and circulating inflammatory proteins. MethodsIn this study, Mendelian randomization (MR) was used to explore the potential causal effect of 91 circulating inflammatory proteins on 3 different types of encephalitis. Causal effects were examined using Steiger, MR-Egger, weighted median, and inverse variance weighting (IVW) methods. IVW methods were primarily used for results interpretation. In addition, sensitivity analyses were performed, including assessment of heterogeneity, horizontal pleiotropy, and Leave-one-out techniques. ResultsWe subjected 91 circulating inflammatory proteins to MR analysis of causality with each of the three types of encephalitis. The results suggested that the inflammatory factors with a potential causal relationship with viral encephalitis were caspase 8, C-X-C motif chemokine 6, interleukin-10, interleukin-15 receptor subunit alpha, interleukin-7, and TNF-beta. Inflammatory factors potentially causally associated with acute disseminated encephalomyelitis are beta-nerve growth factor, cystatin D, interleukin-7,Latency-associated peptide transforming growth factor beta 1,and neurotrophin-3.Inflammatory factors potentially causally associated with autoimmune encephalitis are C–C motif chemokine 25, hepatocyte growth factor, latency-associated peptide transforming growth factor beta 1, programmed cell death 1 ligand 1, sulfotransferase 1A1, and tumor necrosis factor. ConclusionThis finding identifies potential causal effects of certain circulating inflammatory factors on susceptibility to three types of encephalitis. It also suggests the therapeutic potential of modulating the levels of these cytokines. A basis for further research is provided.

Association between dried fruit intake and kidney function: research from univariate and multivariate Mendelian randomized studies

ObjectivesObservational studies have identified an association between dried fruit intake and kidney function. However, these studies have limitations such as vulnerability to confounders and reverse causality bias. Therefore, this study aimed to explore the potential causal relationship between dried fruit intake and kidney function.MethodsA two-sample Mendelian randomization (MR) study was conducted using a large-scale genome-wide association study dataset to investigate the causal relationship between dried fruit intake and kidney function markers (blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), cystatin C (CyC), hematuria, microalbuminuria). The main analytical method was inverse variance weighting. In addition, we applied the MR Egger and weighted median to assess the robustness of the results. Finally, Multivariate Mendelian randomization (MVMR) was used to estimate the direct effect of dried fruit intake on kidney function markers.ResultsThe univariate MR analysis showed that increased dried fruit intake was associated with lower kidney function markers, including BUN (β: −0.171, 95% confidence interval (CI): −0.239 to −0.102, p = 1.063 × 10−6), CR (β: −0.205, 95% CI: −0.311 to −0.099, p = 1.455 × 10−4), UA (β = −0.317, 95% CI: −0.384 to −0.249, p = 4.439 × 10−20), and CysC (β = −0.323, 95% CI: −0.384 to −0.249, p = 1.074 × 10−11); however, it was unrelated to hematuria and microalbuminuria. Causality persisted after performing MVMR analysis; however, with the addition of alcohol consumption and smoking as exposure factors, the causality for UA (β = −0.296, 95% CI: −0.523 to −0.068, p = 1.094 × 10−2) and CysC (β = −0.238, 95% CI: −0.465 to −0.011, p = 4.024× 10−2) weakened, while the causality for BUN (β = −0.038, 95% CI: −0.215 to 0.138, p = 6.698 × 10−1) and CR (β = −0.038, 95% CI: −0.431 to 0.046, p = 1.347 × 10−1) disappeared.ConclusionIncreased dried fruit intake was associated with lower kidney function markers (BUN, CR, UA, and CysC) in the absence of smoking and alcohol consumption; however, the causal relationship between dried fruit intake and BUN and CR disappeared in the presence of smoking and alcohol consumption. These results provide a promising avenue for delaying the course of chronic kidney disease.

Identifying Factors of Dynamic Positioning Incidents through Association Rule Mining

Accidents in the offshore industry can have severe repercussions for people, cargo, vessels, and the environment, making maritime safety a crucial concern. Dynamic positioning incidents, particularly those involving loss of position, represent a significant risk. This study employs association rule mining to analyze DP incident data, leveraging its strength in discovering robust associations. Using the Apriori algorithm, the analysis identifies strong association rules for loss of position (drift-off, drive-off) and loss of redundancy situations. The findings reveal event-related variables and potential causal relationships, providing insights and guidance for reducing the risk and occurrence of future DP incidents through stringent and targeted safety measures.

Helicobacter pylori infection and inflammatory bowel disease: a 2-sample Mendelian randomization study

IntroductionObservational studies have discovered a contradictory phenomenon between Helicobacter pylori (H. pylori) infection and inflammatory bowel disease (IBD). The study aimed to confirm the causal association between H. pylori and IBD, including ulcerative colitis (UC) and Crohn's disease (CD).MethodsWe conducted a Mendelian randomization (MR) study with two sample Genome-Wide Association Studies (GWAS) to determine whether there is a causal relationship between H. pylori infection and IBD, as well as the possible pathogenic factors that may be involved. The reliability of the main MR assumptions was examined through a series of sensitivity analyses.ResultsTwo genetic variants (SNPs) previously identified were employed as instrumental variables (IVs) for H. pylori infection. GWAS data for IBD, UC, and CD were obtained from the recent DF10 release10 of the FinnGen study. Our findings indicated a significant association between H. pylori seropositivity and an increased risk of IBD and UC (IBD: OR: 1.16, 95% CI, 1.03–1.31, P < 0.05; UC: OR: 1.22, 95% CI, 1.08–1.37, P < 0.001) while no causal relationship with CD (P > 0.05). Analysis of the main virulence pathogenic factors revealed a causal relationship between cytotoxin-associated protein A (CagA) and IBD and UC (IBD: OR: 1. 06, 95% CI, 1.001–1.11, P < 0.05; UC: OR: 1.07, 95% CI, 1.004–1.14, P < 0.05), while no correlation was found for vacuolar cytotoxin A (VacA) (P > 0.05). After applying the False Discovery Rate (FDR) correction, the causal relationship between CagA and the risk of IBD or UC was no longer statistically significant.ConclusionThis study suggests a potential causal relationship between H. pylori infection and IBD, particularly UC. The effect may be more pronounced in individuals with previous H. pylori infections.

The role of genetically predicted serum iron levels on neurodegenerative and cardiovascular traits.

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson's disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide.

Association Between Glaucoma and Brain Structural Connectivity Based on Diffusion Tensor Tractography: A Bidirectional Mendelian Randomization Study.

Glaucoma is a neurodegenerative ocular disease that is accompanied by cerebral damage extending beyond the visual system. Recent studies based on diffusion tensor tractography have suggested an association between glaucoma and brain structural connectivity but have not clarified causality. To explore the causal associations between glaucoma and brain structural connectivity, a bidirectional Mendelian randomization (MR) study was conducted involving glaucoma and 206 diffusion tensor tractography traits. Highly associated genetic variations were applied as instrumental variables and statistical data were sourced from the database of FinnGen and UK Biobank. The inverse-variance weighted method was applied to assess causal relationships. Additional sensitivity analyses were also performed. Glaucoma was potentially causally associated with alterations in three brain structural connectivities (from the SN to the thalamus, from the DAN to the putamen, and within the LN network) in the forward MR analysis, whereas the inverse MR results identified thirteen brain structural connectivity traits with a potential causal relationship to the risk of glaucoma. Both forward and reverse MR analyses satisfied the sensitivity test with no significant horizontal pleiotropy or heterogeneity. This study offered suggestive evidence for the potential causality between the risk of glaucoma and brain structural connectivity. Our findings also provided novel insights into the neurodegenerative mechanism of glaucoma.

Cannabis use disorder increases risk of large-artery atherosclerotic stroke and migraine with aura through mendelian randomization study

Observational studies have shown some association between cannabis use disorder (CUD) and neurological disorders, but their causal relationship is unclear. In this study, we tested the potential causal relationship between CUD and three common neurological disorders using two-sample Mendelian randomization (TSMR) and multivariate MR (MVMR) methods. Thirty-two genetic loci were extracted as exposure factors from the largest genome-wide association study (GWAS) summary statistics for CUD to date. TSMR results showed that genetic prediction of CUD with all stroke, ischemic stroke, large-artery atherosclerotic stroke, migraine with aura, and Alzheimer’s disease (AD) had a positive causal relationship (P < 0.05), which was not found in several other diseases. The association between CUD and stroke, ischemic stroke, and AD in the MVMR study may have been influenced by confounding factors (P > 0.05). Subgroup analyses highlighted a causal relationship between genetically predicted CUD and large-artery atherosclerotic stroke (OR = 1.169; 95%CI 1.030–1.328; P = 0.016) and migraine with aura (OR = 1.142; 95% 1.021–1.278; P = 0.020). Our further functional mapping and annotation enrichment analyses using FUMA suggest that the brain-gut axis may serve as another layer of explanation for the existence of an association between CUD and neurological disorders.

Association of aging related genes and immune microenvironment with major depressive disorder

ObjectiveTo study the relationship between aging related genes (ARGs) and Major Depressive Disorder (MDD). MethodsThe datasets GSE98793, GSE52790 and GSE39653 for MDD were obtained from the GEO database, and ARGs were obtained from the Human Aging Genome Resources database. Differential expression genes (DEGs) screening and GO, KEGG enrichment analysis were performed to uncover the underlying mechanisms. To identify key ARGs associated with MDD (key ARG-DEGs), we employed machine learning methods such as LASSO, SVM, and Random Forest, as well as the plug-ins CytoHubba-MCC and MCODE methods. SsGSEA was used to analyze the immune infiltration of MDD and healthy controls. Furthermore, we created risk prediction nomograms model and ROC curves to assess not only the ability of key ARG-DEGs to diagnose MDD, but also predicted miRNAs and transcription factors (TFs) that might interact. Finally, a two-sample Mendelian randomization (MR) study was performed to confirm the association of identified key ARG-DEGs with depression. ResultsDEGs of ARGs between MDD and healthy controls led to the identification of eight ARG-DEGs. GO and KEGG analysis revealed that the pathways associated with these eight ARG-DEGs were primarily concentrated in Foxo pathway, JAK-STAT pathway, Pl3K-AKT pathway, and metabolic diseases. A comprehensive analysis further narrowed down the 8 ARG-DEGs to 4 key ARG-DEGs: MMP9, IL7R, S100B, and EGF. Immune infiltration analysis indicated significant differences in CD8(+) T cells, macrophages, neutrophils, Th2 cells, and TIL cells between MDD and control groups, correlating with these four key ARG-DEGs. Based on these four key ARG-DEGs, a risk prediction model for MDD was developed. The miRNA-TF-mRNA interaction network of the key ARG-DEGs highlights the complexity of the regulatory process, providing valuable insights for future related research. The MR study suggested a potential causal relationship between MMP9 and the risk of depression. ConclusionThe process of aging, immune dysregulation, and MDD are closely interconnected. MMP9, IL7R, S100B, and EGF may be used as novel diagnostic biomarkers and potential therapeutic targets for MDD, especially MMP9.

Causal relationship between IgA nephropathy and common neuropsychiatric disorders: A two-sample Mendelian randomization analysis

ObjectiveUtilizing two-sample Mendelian randomization (TSMR), this study seeks to determine the causal relationship between IgA nephropathy and five prevalent neuropsychiatric disorders. By exploring the genetic associations between IgA nephropathy and neuropsychiatric disorders, this research aims to contribute to the prevention of neuropsychiatric disorders in patients with IgA nephropathy. MethodsPublic genome-wide association study databases were searched, with IgA nephropathy as the exposure factor, including 15,587 patients with IgA nephropathy and 462,197 healthy controls. The outcome factors were five common neuropsychiatric disorders (bipolar disorder, depressive disorder, schizophrenia, anorexia nervosa, and Alzheimer's disease), with outcome data drawn from five datasets in the PGC and GWAScatalog databases. Inverse-variance weighting served as the primary method for causal effect estimation, supplemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity was tested using Cochran's Q test, and sensitivity analysis was conducted using MR-Egger and MR-presso. ResultsMR analysis indicated a positive causal relationship between IgA nephropathy and depressive disorder (OR = 1.010, 95%CI: 1.003–1.017, P = 3.27 × 10−3), and a potential positive causal relationship between IgA nephropathy and anorexia nervosa (OR = 1.165, 95%CI: 1.030–1.319, P = 0.015). ConclusionThere is a positive causal relationship between IgA nephropathy and depressive disorder, and a potential positive causal relationship with anorexia nervosa. No causal relationship was found with schizophrenia, bipolar disorder, or Alzheimer's disease.

Genetic and therapeutic for oral lichen planus and diabetes mellitus: a comprehensive study

BackgroundThis study employed a bidirectional Mendelian Randomization (MR) approach to explore the causal relationships between Oral Lichen Planus (OLP), diabetes mellitus (DM), and glycemic control. It also aims to identify potential pharmacological and herbal treatments that effectively address both OLP and the metabolic dysfunctions associated with DM.MethodsThis study employs a two-way MR approach to investigate the potential causal relationships between diabetes type and glycated hemoglobin (HbA1c) levels, and the risk of OLP. We analyzed differentially expressed genes from the OLP dataset in the Genomics Expression Omnibus (GEO) database, cross-referencing these with HbA1c-related genes for enrichment analysis. Additionally, the Drug-Gene Interaction Database (DGIdb) and Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) were utilized to assess the effectiveness of specific drugs, herbs, and ingredients in treating OLP while managing blood glucose levels.ResultsThe MR analysis revealed a significant association between Type 1 Diabetes mellitus (T1DM) and an increased risk of OLP, unlike Type 2 Diabetes mellitus (T2DM). This finding indicates a unique immunological interaction in T1DM that may predispose individuals to OLP. The drug prediction analysis focused on core targets linked to OLP and HbA1c, evaluating the therapeutic potential of retinoic acid, prednisone, and thalidomide for treating OLP and regulating blood glucose levels. Additionally, herbal medicines such as Ecliptae herbaand Amygdalus communis vas, along with herbal ingredients like quercetin, luteolin, and 17-beta-estradiol, were identified for their anti-inflammatory properties and potential to mitigate metabolic dysfunction in diabetes.ConclusionThe study highlighted a complex interplay between diabetes and OLP, underscoring the efficacy of integrated therapeutic strategies that target both conditions. The findings suggest that both pharmaceutical and herbal treatments can effectively manage the clinical manifestations of OLP and associated metabolic challenges. This holistic approach to treatment could significantly enhance patient outcomes by addressing the interconnected aspects of these chronic conditions.

Association of cardiovascular disease and urate levels with aortic aneurysm: a bilateral mendelian randomization study

The aim of this study is to investigate the potential causal relationships between coronary artery disease (CAD), myocardial infarction (MI), urate levels, and aortic aneurysm (AA), abdominal aortic aneurysm (AAA), thoracic aortic aneurysm(TAA), aortic dissection (AD) in individuals of European ancestry. To examine the potential causal relationships between CAD, MI, and urate levels with AA, AAA, TAA, AD, respectively, we performed a two-sample Mendelian randomization (MR) analysis. Genetic instruments that reached genome-wide significance (p < 5 × 10 − 8) for risk factors were obtained from genome-wide association studies(GWASs) conducted on individuals of European origin. On the other hand, genetic instruments of AA, AAA, TAA or AD were chosen from the FinnGen cohort. The primary analysis employed the inverse-variance weighted MR method, while sensitivity analyses were conducted using MR-Egger, weighted median MR, MR pleiotropy residual sum and outlier, and Phenoscanner searching. In addition, we performed the MR-Egger intercept analysis to identify potential pleiotropy and utilized Cochran’s Q statistics to evaluate heterogeneity. Additionally, we conducted bidirectional Mendelian randomization experiments to mitigate the potential influence of reverse causation. According to the results of our study, there were statistically significant higher risks for AA in relation to CAD/MI(odds ratio (OR) with 95% confidence interval (CI): 1.309 (1.150–1.490), and 1.255 (1.147–1.373). Similarly, there were statistically significant higher risks for AAA in relation to CAD and MI (OR with 95% CI: 1.383 (1.189–1.609), and 1.352 (1.178–1.552). The sensitivity analysis demonstrated that the causative effects of CAD/MI, and AA /AAA, were robust. A positive causal link was observed between CAD/MI, and AA/AAA. Nevertheless, no causal link was found between CAD, MI, urate levels, and TAA .

Partnership quality and maternal depressive symptoms in the transition to parenthood: a prospective cohort study

BackgroundPregnancy and childbirth are critical life events which lead to significant changes in family structures and roles, thus having a substantial impact on partner relationship and maternal wellbeing. A dysfunctional partnership during this critical time of life has been associated with maternal depressiveness. However, sub-components of partnership quality and the causal relation with maternal symptoms of depression in the perinatal period have been sparsely studied so far. The current study aims to longitudinally assess the course of relationship quality and its sub-components from pregnancy to postpartum and to test a potential causal association with maternal symptoms of depression in the perinatal period.MethodsDiffering from previous studies, partnership quality and symptoms of depression have been assessed prospectively and longitudinally from an early stage of pregnancy (second trimester) until six months postpartum. Cross-lagged panel models were applied to investigate a potential causal relationship between partnership quality and maternal depressive symptoms.ResultsRelationship quality decreased significantly during the transition to parenthood (p < .05) with the steepest decline referring to tenderness (p < .001). We also found a substantial association of relationship quality and maternal depressiveness, but no indication for a clear causal direction of this association.ConclusionsOur results suggest that relationship quality and maternal depressiveness are substantially related in the perinatal period, thus pointing to the need of early prevention and intervention programs for peripartum women and their partners to prevent adverse outcome for the couple and the family.

The role of mitochondrial DNA copy number in autoimmune disease: a bidirectional two sample mendelian randomization study.

Mitochondrial DNA (mtDNA) plays an important role in autoimmune diseases (AD), yet the relationship between mitochondria and autoimmune disease is controversial. This study employed bidirectional Mendelian randomization (MR) to explore the causal relationship between mtDNA copy number and 13 ADs (including ankylosing spondylitis [AS], Crohn's disease [CD], juvenile rheumatoid arthritis [JRA], polymyalgia rheumatica [PMR], psoriasis [PSO], rheumatoid arthritis [RA], Sjogren's syndrome [SS], systemic lupus erythematosus [SLE], thyrotoxicosis, type 1 diabetes mellitus [T1DM], ulcerative colitis [UC], and vitiligo). A two-sample MR analysis was performed to assess the causal relationship between mtDNA copy number and AD. Genome-wide association study (GWAS) for mtDNA copy number were obtained from the UK Biobank (UKBB), while those associated with AD were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was the primary analysis method, complemented by three sensitivity analyses (MR-Egger, weighted median, weighted mode) to validate the results. IVW MR analysis identified significant associations between mtDNA copy number and CD (OR=2.51, 95% CI 1.56-4.22, P<0.001), JRA (OR=1.87, 95% CI 1.17-7.65, P=0.022), RA (OR=1.71, 95%CI 1.18-2.47, P=0.004), thyrotoxicosis (OR=0.51, 95% CI0.27-0.96, P=0.038), and T1DM (OR=0.51, 95% CI 0.27-0.96, P=0.038). Sensitivity analyses indicated no horizontal pleiotropy. Our study revealed a potential causal relationship between mtDNA copy number and ADs, indicating that these markers may be relevant in exploring new therapeutic approaches.

Oral Disease and Atherosclerosis May Be Associated with Overlapping Metabolic Pathways.

Dental caries and periodontitis are among the most prevalent chronic diseases worldwide and have been associated with atherosclerotic cardiovascular diseases (ASCVD). This study aimed to determine (1) the independent associations between subclinical ASCVD markers (carotid intima media thickness [CIMT] and coronary artery calcification [CAC]) and quantitative indices of oral disease including the decayed, missing, and filled teeth (DMFT) index, gingivitis parameters, periodontal status, and number of teeth lost and (2) the extent to which metabolites altered in individuals with oral disease overlapped with those altered in individuals with ASCVD. We used data from 552 participants recruited through the Dental Strategies Concentrating on Risk Evaluation project. Oral examinations were conducted, and CIMT and CAC were measured. Multiple linear regression models were constructed with CIMT and CAC as dependent variables in the epidemiologic analysis. In the metabolomic analysis, logistic or linear regression was used to test 1,228 metabolites for association with each phenotype adjusted for age, sex, race, blood pressure, smoking, diabetes, cholesterol, high-sensitivity C-reactive protein, and interleukin-6. None of the oral disease markers were significant predictors of ASCVD markers in the fully adjusted models. However, critical lipid and lipid-signaling pathway metabolites were significantly associated with gingivitis, periodontitis, and DMFT: the lysophospholipid pathway (odds ratio [OR] = 2.29, false discovery rate [FDR]-adjusted P = 0.038) and arachidonate with gingivitis (OR = 2.35, FDR-adjusted P = 0.015), the sphingolipid metabolism pathway with periodontitis (OR = 2.09, FDR-adjusted P = 0.029), and borderline associations between plasmalogen and lysophospholipid pathways and DMFT (P = 0.055). Further, the same metabolite from the sphingolipid metabolism pathway, sphingomyelin (d17:1/14:0, d16:1/15:0), was inversely associated with both CIMT (β = -0.14, FDR-adjusted P = 0.014) and gingivitis (OR = 0.04, FDR-adjusted P = 0.033). The discovery of a common sphingomyelin metabolite in both disease processes is a novel finding suggesting that gingivitis and periodontitis may be associated with some overlapping metabolic pathways associated with ASCVD and indicating potential shared mechanisms among these diseases. The same metabolites may be altered in atherosclerosis and oral disease. Specifically, a common sphingomyelin metabolite was inversely associated with gingivitis and carotid intima media thickness, a subclinical marker of atherosclerotic cardiovascular disease. These findings can provide valuable insights for future mechanistic studies to establish potential causal relationships, with the hope of influencing disease prevention and targeted early treatment.