Bidirectional Two-sample Mendelian Randomization Research Articles

A bidirectional two-sample Mendelian randomization study to evaluate the relationship between psoriasis and interstitial lung diseases

BackgroundPrior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD.MethodsData regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms— MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode— to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method.ResultsThe analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes.ConclusionOur findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD.

Causal relationships between psychological disorders and functional gastrointestinal disorders: a bidirectional two-sample Mendelian randomization study.

Observational studies have shown bidirectional associations between psychological disorders (e.g. depression and anxiety) and functional gastrointestinal disorders. However, whether the relationships are causal is uncertain. Here, we used a bidirectional two-sample Mendelian randomization method to investigate the association between psychological disorders and functional gastrointestinal disorders (FGIDs). We obtained genome-wide association study summary statistics for two common psychological disorders: depression (170 756 cases) and anxiety (31 977 cases), as well as for three common FGIDs: functional dyspepsia with 6666 cases, constipation with 26 919 cases, and irritable bowel syndrome (IBS) with 7053 cases. These summary statistics were retrieved from several publicly available genome-wide association study databases. The inverse variance weighted method was used as the main Mendelian randomization method. Inverse variance weighted Mendelian randomization analyses showed statistically significant associations between genetically predicted depression and risk of functional dyspepsia [odds ratio (OR): 1.40, 95% confidence interval (CI): 1.08-1.82], constipation (OR: 1.28, 95% CI: 1.13-1.44), and IBS (OR: 1.51, 95% CI: 1.37-1.67). Genetically predicted anxiety was associated with a higher risk of IBS (OR: 1.13, 95% CI: 1.10-1.17) instead of functional dyspepsia and constipation. In addition, genetically predicted IBS instead of functional dyspepsia and constipation was associated with a higher risk of depression (OR: 1.33, 95% CI: 1.12-1.57) and anxiety (OR: 2.05, 95% CI: 1.05-4.03). Depression is a causal risk factor for three common FGIDs. A bidirectional causal relationship between IBS and anxiety or depression was also identified.

Causal linkage between angiotensin-converting enzyme 2 and risk of lung cancer: a bidirectional two-sample Mendelian randomization study.

Observational studies suggest a connection between ACE2 (angiotensin-converting enzyme 2) and lung cancer. However, it's not apparent if confounding variables are interfering with the link. Therefore, we aimed to define the relationships between ACE2 and the risk of lung cancer. With the aim of developing genetic tools, we selected SNPs substantially associated with ACE2 using a statistically significant criterion. The relevant SNPs were then taken from the lung cancer GWAS dataset for additional research. After that, we used two-sample Mendelian randomization (MR) to ascertain if ACE2 is causally linked to the risk of developing lung cancer. To investigate the causal links' directions, we also performed a reverse MR analysis. According to our findings, there is strong evidence that ACE2 is linked to a decreased chance of developing lung cancer (odds ratio: 0.94; 95% confidence interval: 0.90-0.98; P = 0.0016). The IVW method, the major MR analysis, was not impacted by heterogeneity in any of the analyses, according to Cochrane's Q test ( = 0.207). The MR-Egger intercept (P intercept = 0.622) showed no indication of horizontal pleiotropy in any of the investigations. Outlier SNPs were not detected by the MR-PRESSO global test (P globaltest = 0.191). The leave-one-out analysis was performed, and the results showed a steady outcome. Nonsignificant causal estimates between lung cancer and ACE2 were produced by reverse MR analysis. MR investigation revealed a significant causal link between ACE2 and the risk of getting lung cancer. These findings may have implications for public health measures aimed at reducing the incidence of lung cancer.

Genetic evidence for causal association between migraine and dementia: a mendelian randomization study

BackgroundThere is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer’s disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB).MethodsSummary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran’s Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis.ResultsMigraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02–0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02–0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings.ConclusionOur study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Relationship between Sjogren's syndrome and gastroesophageal reflux: A bidirectional Mendelian randomization study

The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MR‒Egger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312–1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651–1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.

Exploring the bidirectional causal associations between pain and circulating inflammatory proteins: A Mendelian randomization study.

Multisite chronic pain (MCP) and site-specific chronic pain (SSCP) may be influenced by circulating inflammatory proteins, but the causal relationship remains unknown. To overcome this limitation, two-sample bidirectional Mendelian randomization (MR) analysis was used to analyse data for 91 circulating inflammatory proteins, MCP and SSCP encompassing headache, back pain, shoulder pain, hip pain, knee pain, stomach abdominal pain and facial pain. The primary MR method used was inverse variance weighting, sensitivity analyses included weighted median, MR pleiotropy residual sum and outlier and the Egger intercept method. Heterogeneity was also detected using Cochrane's Q test and leave-one-out analyses. Finally, a causal relationship between 29 circulating inflammatory proteins and chronic pain was identified. Among these proteins, 14 exhibited a protective effect, including MCP (T-cell surface glycoprotein cluster of differentiation 5), headache (4E-binding protein 1 [4EBP1], cluster of differentiation 40, cluster of differentiation 6 and C-X-C motif chemokine [CXCL] 11), back pain (leukaemia inhibitory factor), shoulder pain (fibroblast growth factor [FGF]-5 and interleukin [IL]-18R1), stomach abdominal pain (tumour necrosis factor [TNF]-α), hip pain (CXCL1, IL-20 and signalling lymphocytic activation molecule 1) and knee pain (IL-7 and TNF-β). Additionally, 15 proteins were identified as risk factors for MCP and SSCP: MCP (colony-stimulating factor 1, human glial cell line-derived neurotrophic factor and IL-17C), headache (fms-related tyrosine kinase 3 ligand, IL-20 receptor subunit α [IL-20RA], neurotrophin-3 and tumour necrosis factor receptor superfamily member 9), facial pain (CXCL1), back pain (TNF), shoulder pain (IL-17C and matrix metalloproteinase-10), stomach abdominal pain (IL-20RA), hip pain (C-C motif chemokine 11/eotaxin-1 and tumour necrosis factor ligand superfamily member 12) and knee pain (4EBP1). Importantly, in the opposite direction, MCP and SSCP did not exhibit a significant causal impact on circulating inflammatory proteins. Our study identified potential causal influences of various circulating inflammatory proteins on MCP and SSCP and provided promising treatments for the clinical management of MCP and SSCP.

Dissecting causal relationships between gut microbiota, blood metabolites, and glioblastoma multiforme: a two-sample Mendelian randomization study.

Given the increasing interest in the role of gut microbiota in glioblastoma multiforme (GBM), our objective was to examine the potential causal relationship between gut microbiota and GBM, as well as the mediating effects of specific metabolites. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the associations between 196 microbial taxa and GBM. A two-step MR technique was used to identify significant mediators in this relationship. Subsequently, a mediation analysis was performed to explore and quantify the mediating effects of specific metabolites on the causal relationship between gut microbiota and GBM. Five taxa showed significant associations with GBM. Among them, family Victivallaceae [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.21, 3.13; p = 0.005] and genus Lactococcus (OR: 1.81; 95% CI: 1.04, 3.15; p = 0.036) were positively correlated with the risk of GBM, while phylum Cyanobacteria had a protective effect against GBM (OR: 0.45; 95% CI: 0.22, 0.89; p = 0.021). The mediation analysis revealed that the connections among family Victivallaceae, genus Lactococcus, phylum Cyanobacteria and GBM were mediated by Methyl-4-hydroxybenzoate sulfate, phosphoethanolamine and dehydroepiandrosterone sulfate. Each of these accounted for 7.27, 7.98, and 8.65%, respectively. Our study provides evidence supporting a potential causal association between certain gut microbiota taxa and GBM. The study highlights the central role of gut microbiota in GBM pathogenesis and their interactions with vital serum metabolites. This paves the way for potential novel therapeutic interventions in GBM management.

Association between glioma and neurodegenerative diseases risk: a two-sample bi-directional Mendelian randomization analysis.

Earlier observational studies have demonstrated a correlation between glioma and the risk of neurodegenerative diseases (NDs), but the causality and direction of their associations remain unclear. The objective of this study was to ascertain the causal link between glioma and NDs using Mendelian randomization (MR) methodology. Genome-wide association study (GWAS) data were used in a two-sample bi-directional MR analysis. From the largest meta-analysis GWAS, encompassing 18,169 controls and 12,488 cases, summary statistics data on gliomas was extracted. Summarized statistics for NDs, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) were obtained from the GWAS of European ancestry. Inverse variance weighted (IVW) method was elected as the core MR approach with weighted median (WM) method and MR-Egger method as complementary methods. In addition, sensitivity analyses were performed. A Bonferroni correction was used to correct the results. Genetically predicted glioma had been related to decreased risk of AD. Specifically, for all glioma (IVW: OR = 0.93, 95% CI = 0.90-0.96, p = 4.88 × 10-6) and glioblastoma (GBM) (IVW: OR = 0.93, 95% CI = 0.91-0.95, p = 5.11 × 10-9). We also found that genetically predicted all glioma has a suggestive causative association with MS (IVW: OR = 0.90, 95% CI = 0.81-1.00, p = 0.045). There was no evidence of causal association between glioma and ALS or PD. According to the results of reverse MR analysis, no discernible causal connection of NDs was found on glioma. Sensitivity analyses validated the robustness of the above associations. We report evidence in support of potential causal associations of different glioma subtypes with AD and MS. More studies are required to uncover the underlying mechanisms of these findings.

Causal relationship between thyroid dysfunction and sepsis: a bidirectional two-sample Mendelian randomization

To explore the causal relationship between thyroid dysfunction and sepsis based on the bidirectional two-sample Mendelian randomization (MR) method. The genome-wide association study (GWAS) dataset were selected to screen single nucleotide polymorphisms (SNP) associated with thyroid dysfunction as instrumental variable (IV) for genetic variation, using hypothyroidism and hyperthyroidism as exposure factor and sepsis as outcome factor. Potential causal relationship between thyroid dysfunction and sepsis was analyzed using a bidirectional two-sample MR method primary analysis method of inverse-variance weighted (IVW). Potential pleiotropic analysis of SNP was performed using the MR Egger regression intercept test. Sensitivity analysis was performed using the "leave one out" test. Reverse MR method was used to prove the causal relationship. The GWAS data were screened based on the three main assumptions of MR, resulting in 101 SNP strongly associated with hypothyroidism and 10 SNP strongly associated with hyperthyroidism entering the MR analysis. The results of the MR using the IVW method showed that the risk of sepsis in individuals with hypothyroidism was 2.293 times higher than those without hypothyroidism [odds ratio (OR) = 2.293, 95% confidence interval (95%CI) was 1.199-4.382, P = 0.012]. There was no significant difference in the risk of sepsis between hyperthyroid and non-hyperthyroid populations (OR = 1.049, 95%CI was 0.999-1.100, P = 0.560). MR Egger regression intercept test showed that the included SNP did not have pleiotropy, and the MR-PRESSO test did not find outliers. Sensitivity analysis suggested that the results of MR were stable. The results of the reverse MR analysis showed that the reverse causal relationship between hyperthyroidism and sepsis was not proved (OR = 0.996, 95%CI was 0.988-1.004, P = 0.338), which further confirmed the robust MR analysis result. The results of the bidirectional two-sample MR analysis show that hypothyroidism can increase the risk of sepsis onset, while there is no causal relationship between hyperthyroidism and sepsis.

Causality of immune cells on primary sclerosing cholangitis: a bidirectional two-sample Mendelian randomization study.

Observational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood. A bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran's Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy. In forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032-1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086-1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630-0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823-0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28- CD127- CD25++ CD8+ T cell AC, CD28- CD25++ CD8+ T cell AC, CD28- CD8+ T cell/CD8+ T cell, CD28- CD8+ T cell AC, and CD45 RA- CD28- CD8+ T cell AC. Our study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

Causal Relationship Between Obstructive Sleep Apnea and Temporomandibular Disorders: A Bidirectional Mendelian Randomization Analysis.

This study was conducted to investigate the bidirectional causal relationship between obstructive sleep apnea (OSA) and temporomandibular disorders (TMD). Using an online pooled dataset of genome-wide association studies (GWAS), a two-sample bi-directional Mendelian randomization (MR) method was implemented. Inverse variance weighting was used as the primary analyses approach, and other methods of MR Egger, weighted median method, MR-Egger, Simple mode, and Weighted mode analysis were conducted as supplements to evaluate the causal relationship between OSA and TMD with odds ratios (OR) and 95% confidence interval (CI). Furthermore, the Cochran Q, MR-Egger, and MR-PRESSO approaches were used to perform the heterogeneity test and multiple validity. The general results of the forward MR analysis indicated that OSA had a significant causal influence on TMD (OR=1.241, 95% CI: 1.009-1.526, P=0.041), but no significant correlation was observed in the reverse MR analysis (IVW: OR=0.975, 95% CI=0.918-1.036, P=0.411). In summary, our research demonstrated a hereditary causative relationship between OSA and TMD, indicating that appropriate intervention is required for both prevention and treatment of TMD.

Bi-directional two-sample Mendelian randomization identifies causal association of depression with temporomandibular disorders.

Depression and anxiety have been suggested to be associated with temporomandibular disorders (TMD) in observational studies. However, the causal association and the direction in the relationship between depression/anxiety and TMD remain unknown. This study investigated the potential causal relationship between depression/anxiety and TMD with two-sample bi-directional Mendelian randomization (MR). Summary statistics of depression (N = 500 199), anxiety disorder (N = 17 310) and TMD (N = 195 930) were sourced from large-scale genome-wide association studies (GWAS). The primary Mendelian randomization (MR) estimation employed the inverse-variance weighted meta-analysis (IVW). Additional MR sensitivity methods and multivariate MR (MVMR) were applied to address pleiotropy. IVW results indicated a causal effect of genetically predicted depression on TMD (OR = 1.887, 95% CI = 1.504-2.367, p < .001), which was supported by other sensitivity MR approaches. MVMR results suggested that the negative effect of depression on TMD persisted after conditioning on other potential confounders. The association of anxiety disorder with TMD was not supported by our findings. In the reverse direction, we did not find compelling evidence suggesting the causal effect of TMD on depression and anxiety disorder. The present study suggests a potential causal association between genetic liability for depression and the risk of TMD. Our MR findings align with prior epidemiological research, underscoring the significance of early detection and prevention of depression in the treatment of TMD.

Exploring the Causal Relationship Between Migraine and Insomnia Through Bidirectional Two-Sample Mendelian Randomization: A Bidirectional Causal Relationship.

The intricate relationship between migraine and insomnia has been a subject of great interest due to its complex mechanisms. Despite extensive research, understanding the causal link between these conditions remains a challenge. This study employs a bidirectional Mendelian randomization approach to investigate the causal relationship between migraine and insomnia. Risk loci for both conditions were derived from large-scale Genome-Wide Association Studies (GWAS). The primary method of Mendelian Randomization utilized in this study is the Inverse Variance Weighted (IVW) method. Our findings indicate a bidirectional causal relationship between migraine and insomnia. In the discovery set, migraine had a significant effect on insomnia (OR=1.02, 95% CI=1.02 (1.01-1.03), PIVW=5.30E-04). However, this effect was not confirmed in the validation set (OR=1.03, 95% CI=1.03 (0.87-1.21), PIVW=0.77). Insomnia also had a significant effect on migraine (OR=1.02, 95% CI=1.02 (0.01-1.03), PIVW=2.67E-08), and this effect was validated in the validation set (OR=2.30, 95% CI=2.30 (1.60-3.30), PIVW=5.78E-06). This study provides meaningful insights into the bidirectional causality between migraine and insomnia, highlighting a complex interplay between these conditions. While our findings advance the understanding of the relationship between migraine and insomnia, they also open up new avenues for further research. The results underscore the need for considering both conditions in clinical and therapeutic strategies.

Genetic evidence supports a causal relationship between air pollution and brain imaging-derived phenotypes

BackgroundObservational studies have reported associations between air pollutants and brain imaging-derived phenotypes (IDPs); however, whether this relationship is causal remains uncertain. MethodsWe conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the causal relationships between 5 types of air pollutants (N=423,796 to 456,380 individuals) and 587 reliable IDPs (N=33,224 individuals). Two-step MR was also conducted to assess whether the identified effects are mediated through the modulation of circulating cytokines (N=8293). ResultsWe found genetic evidence supporting the association of nitrogen oxides (NOx) with mean intra-cellular volume fraction (ICVF) in the left uncinate fasciculus (IVW β=-0.42, 95 % CI −0.62 to −0.23, P=1.51×10−5) and mean fractional anisotropy (FA) in the left uncinate fasciculus (IVW β=-0.42, 95 % CI −0.62 to −0.21, P=4.89×10−5). In further two-step MR analyses, we did not find evidence that genetic predictions of any circulating cytokines mediated the association between NOx and IDPs. ConclusionThis study provides evidence for the association between air pollutants and brain IDPs, emphasizing the importance of controlling air pollution to improve brain health.

Causal association between phenylalanine and Parkinson's disease: a two-sample bidirectional mendelian randomization study.

Research findings indicate a putative indirect or latent association between phenylalanine (Phe) and Parkinson's disease (PD). In this study, we aimed to analyze the causal relationship between Phe and PD by two sample Mendelian randomization (MR) analysis. In this study, the PD-related dataset and Phe-related dataset were downloaded from Integrative Epidemiology U1nit (IEU) Open Genome-Wide Association Study (GWAS) database. Four algorithms (MR Egger, maximum likelihood, inverse variance weighting (IVW) and unweighted regression) were used to perform MR analysis. The sensitivity analysis (heterogeneity test, horizontal pleiotropy test and Leave-One-Out (LOO) analysis) was used to assess the reliability of MR analyses. In the forward MR analysis, Phe was a safety factor for PD (p-value < 0.05 and odds ratios (OR) < 1). The results of reverse MR analysis showed that there was no causal relationship between PD and Phe (p-value > 0.05). In addition, sensitivity analysis showed that MR analysis was reliable. The results of this study revealed that Phe was a safety factor for PD, meaning that Phe reduced the risk of PD.

Association between walking pace and heart failure: A Mendelian randomization analysis

Background and aimThe relationship between walking pace and heart failure (HF) has been recognized, yet the directionality and underlying mediating risk factors remain unclear. Methods and resultsThis study utilized bidirectional two-sample Mendelian randomization (MR) with genome-wide association studies (GWAS) summary statistics to assess the causal relationships between walking pace and HF. Additionally, we employed a two-step Multivariable Mendelian Randomization (MVMR) to explore potential mediating factors. We further validated our findings by conducting two-sample MR with another available GWAS summary data on heart failure. Results indicated that genetically predicted increases in walking pace were associated with a reduced risk of HF (odds ratio (OR), 0.589, 95% confidence interval (CI): 0.417–0.832). Among the considered mediators, the waist-to-hip ratio (WHR) accounts for the largest proportion of the effect (45.7%, 95% CI: 13.2%, 78.2%). This is followed by type 2 diabetes at 24.4% (95% CI: 6.7%, 42.0%) and triglycerides at 18.6% (95% CI: 4.5%, 32.7%). Furthermore, our findings reveal that genetically predicted HF risk (OR, 0.975, 95% CI: 0.960–0.991) is associated with a slower walking pace. Validated findings were consistent with the main results. ConclusionsIn conclusion, MR analysis demonstrates that a slow walking pace is a reliable indicator of an elevated risk of HF, and the causal relationship is bidirectional. Interventions focusing on waist-to-hip ratio, type 2 diabetes, and triglycerides may provide valuable strategies for HF prevention in individuals with a slow walking pace.

Causal relationship between Helicobacter pylori infection and IgA nephropathy: a bidirectional two-sample mendelian randomization study

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis, and serum Helicobacter pylori (H. pylori) antibody levels are increased in patients with IgA N, but the role of H. pylori infection in the pathogenesis of IgAN is unclear. In this study, we investigated whether there is a causal relationship and reverse causality between IgAN and H. pylori infection by using a bidirectional two-sample Mendelian randomization (MR) analysis. This study was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods, with the IVW method having the strongest statistical efficacy. Seven common serum H. pylori antibodies were selected as exposure factors for positive MR analysis. The results showed that there was no evidence of a causal relationship between H. pylori infection and IgAN. Reverse MR analysis showed that there was also no evidence that the occurrence of IgAN leads to an increased risk of H. pylori infection.

Snoring and risk of dementia: a prospective cohort and Mendelian randomization study.

The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI). Using data from 451,250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer's disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis. During a median follow-up of 13.6 years, 8,325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI. The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk.

Immune-mediated inflammatory diseases and periodontal disease: a bidirectional two-sample mendelian randomization study

BackgroundPrevious observational studies have shown a bidirectional association between immune-mediated inflammatory disorders (IMID) and periodontal disease. However, evidence regarding the causal role of IMID and periodontal disease is still lacking. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to uncover the potential genetic causal effects between IMID and periodontal disease.MethodsBidirectional two-sample MR analysis was employed. Data for ten IMIDs were sourced from genome-wide association studies (GWAS) conducted by the FinnGen Consortium (range from 1023 to 36321 cases) and UK Biobank (UKB) (range from 150 to 17574 cases). Furthermore, GWAS data for periodontal disease were obtained from the FinnGen Consortium (87497 cases), UKB (458 cases), and Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 periodontitis cases). Subsequently, the causal relationships were analyzed by random effects inverse variance weighting, weighted median, and MR-Egger. Sensitivity analyses were performed using the Cochrane Q test, funnel plot, and Mr-Egger intercept test to ensure robustness. Eventually, replication analysis and meta-analysis across different databases were carried out.ResultsSystemic lupus erythematosus (SLE) [IVW: OR = 1.079 (95% CI: 1.032–1.128) and P < 0.001], Sjogren syndrome [IVW: OR = 1.082 (95% CI: 1.012–1.157) and P = 0.022] and hypothyroidism [IVW: OR = 1.52 (95% CI: 1.13–2.04) and P = 0.005] may increase the risk of periodontal disease. In addition, periodontal disease may reduce the risk of SLE [IVW: OR = 0.8079 (95% CI: 0.6764–0.9650) and P = 0.019] and hyperthyroidism [IVW: OR = 5.59*10–9 (95% CI: 1.43*10–15-2.18*10–2) and P = 0.014]. Meta-analysis indicated a causal correlation between SLE and an increased risk of periodontal disease: [OR = 1.08 (95% CI: 1.03–1.13), P = 0.0009]. No significant evidence suggests bilateral causal relationships between other IMIDs and periodontal disease. No significant estimation of heterogeneity or pleiotropy is detected.ConclusionsOur study has confirmed a genetic causal relationship between IMIDs and periodontal disease, thereby unveiling novel potential mechanisms underlying IMIDs and periodontal disease. This discovery is promising in fostering interdisciplinary collaboration between clinicians and stomatologists to facilitate appropriate and precise screening, prevention, and early treatment of IMIDs and periodontal disease.

Association of ankylosing spondylitis with cardiovascular disease: a bidirectional two-sample mendelian randomization study.

Current observational investigations hint at a potential linkage between ankylosing spondylitis and cardiovascular wellness. However, the nature of this causality remains to be elucidated. Consequently, this study is designed to evaluate the causal interconnection between ankylosing spondylitis and cardiovascular-related conditions utilizing a bidirectional two-sample Mendelian Randomization (MR) methodology. In this study, we conducted Mendelian randomization (MR) analyses using genome-wide association study (GWAS) data. The fixed-effects inverse variance weighted (IVW) model was used as the primary analysis method, and MR-Egger regression and the weighted median method were employed as supplementary approaches. Horizontal pleiotropy and heterogeneity were evaluated using various statistical tests, including MR-PRESSO global test, MR-Egger intercept, and Cochran's Q test. The MR result demonstrated an increased risk of heart failure in individuals with ankylosing spondylitis (OR: 1.0132, 95% CI = 1.0043-1.0221, p = 0.003). The MR analysis results did not demonstrate a causal relationship between ankylosing spondylitis and other cardiovascular diseases, such as atrial fibrillation, coronary artery disease, ischemic stroke, myocardial infarction, and valvular heart disease (all p > 0.05). No evidence of reverse causality was found between ankylosing spondylitis and mentioned cardiovascular diseases in reverse MR analyses. Sensitivity analysis verified the reliability of the results. Our MR study indicates a relationship between ankylosing spondylitis and an increased risk of heart failure. Further research is needed to confirm these findings and elucidate the underlying mechanisms involved.