Mendelian Randomization Methods Research Articles

Association of serum 25-hydroxyvitamin D levels, vitamin D-binding protein levels, and diabetes mellitus: Two-sample Mendelian randomization.

Studies have suggested that Vitamin D deficiency is associated with the occurrence of both type 1 and type 2 diabetes, and that vitamin D-binding proteins (VDBP) are necessary for metabolic stress in pancreatic α-cells. However, the causal relationship between serum 25-hydroxyvitamin D [25(OH)D] levels, VDBP, and the risk of diabetes mellitus (DM) remains unclear. Mendelian randomization (MR) was used to investigate the causal relationship between 25(OH)D, VDBP, and DM. Relevant recent data were downloaded from the NHGRI-EBI Catalog of published genome-wide association studies (GWAS) and filtered for single nucleotide polymorphisms (SNPs). We used multiple MR methods, including inverse variance weighting (IVW), and performed sensitivity analyses to detect whether pleiotropy or heterogeneity biased the results. There was a causal relationship between genetically predicted VDBP levels and serum 25(OH)D levels, and serum 25(OH)D levels increased with increasing VDBP levels (IVW: β = 0.111, OR = 1.117, 95% CI:1.076-1.162, P = 1.41 × 10-8). There was no causal relationship between the genetically predicted VDBP levels, serum 25(OH)D levels, and DM (VDBP: IVW β:0.001, OR:1.001, 95% CI:0.998-1.003, P > .05; 25(OH)D: IVW β: -0.009, OR:0.991, 95% CI:0.982-1.001, P = .068). Sensitivity analysis indicated that horizontal pleiotropy was unlikely to bias causality in this study. MR analysis results demonstrated a positive causal relationship between VDBP levels and serum 25(OH)D levels in the European population. The 25(OH)D and VDBP levels were not causally related to an increased risk of diabetes.

Rheumatoid arthritis and the risk of chronic kidney diseases: a Mendelian randomization study

BackgroundThe extra-articular lesions of rheumatoid arthritis (RA) are reported to involve multiple organs and systems throughout the body, including the heart, kidneys, liver, and lungs. This study assessed the potential causal relationship between RA and the risk of chronic kidney diseases (CKDs) using the Mendelian randomization (MR) analysis.MethodIndependent genetic instruments related to RA and CKD or CKD subtypes at the genome-wide significant level were chosen from the publicly shared summary-level data of genome-wide association studies (GWAS). Then, we obtained some single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs), which are associated with RA in individuals of European origin, and had genome-wide statistical significance (p5 × 10−8). The inverse-variance weighted (IVW) method was the main analysis method in MR analysis. The other methods, such as weighted median, MR–Egger, simple mode, and weighted mode were used as supplementary sensitivity analyses. Furthermore, the levels of pleiotropy and heterogeneity were assessed using Cochran’s Q test and leave-one-out analysis. Furthermore, the relevant datasets were obtained from the Open GWAS database.ResultsUsing the IVW method, the main method in MR analysis, the results showed that genetically determined RA was associated with higher risks of CKD [odds ratio (OR): 1.22, 95% confidence interval (CI) 1.13–1.31; p < 0.001], glomerulonephritis (OR: 1.23, 95% CI 1.15–1.31; p < 0.000), amyloidosis (OR = 1.43, 95% CI 1.10–1.88, p < 0.001), and renal failure (OR = 1.18, 95% CI 1.00–1.38, p < 0.001). Then, using multiple MR methods, it was confirmed that the associations persisted in sensitivity analyses, and no pleiotropy was detected.ConclusionThe findings revealed a causal relationship between RA and CKD, including glomerulonephritis, amyloidosis, and renal failure. Therefore, RA patients should pay more attention to monitoring their kidney function, thus providing the opportunity for earlier intervention and lower the risk of progression to CKDs.

Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study.

Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ArLD) constitute the primary forms of chronic liver disease, and their incidence is progressively increasing with changes in lifestyle habits. Earlier studies have documented a correlation between the occurrence and development of prevalent mental disorders and fatty liver. To investigate the correlation between fatty liver and mental disorders, thus necessitating the implementation of a mendelian randomization (MR) study to elucidate this association. Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog, while information on mental disorders, including Alzheimer's disease, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple personality disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia was acquired from the psychiatric genomics consortium. A two-sample MR method was applied to investigate mediators in significant associations. After excluding weak instrumental variables, a causal relationship was identified between fatty liver disease and the occurrence and development of some psychiatric disorders. Specifically, the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD (OR: 5.81, 95%CI: 5.59-6.03, P < 0.01), bipolar disorder (OR: 5.73, 95%CI: 5.42-6.05, P = 0.03), OCD (OR: 6.42, 95%CI: 5.60-7.36, P < 0.01), and PTSD (OR: 5.66, 95%CI: 5.33-6.01, P < 0.01). Meanwhile, NAFLD significantly increased the risk of developing bipolar disorder (OR: 55.08, 95%CI: 3.59-845.51, P < 0.01), OCD (OR: 61.50, 95%CI: 6.69-565.45, P < 0.01), and PTSD (OR: 52.09, 95%CI: 4.24-639.32, P < 0.01). Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders, namely bipolar disorder, OCD, and PTSD, highlighting the significance of preventive measures against psychiatric disorders in patients with fatty liver disease.

Exploring the causal association between genetically determined circulating metabolome and hemorrhagic stroke

BackgroundHemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects.MethodsWe assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders.ResultsWe finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40–0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08–0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02–4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09–0.77, PMVMR = 0.015) with significant causal relation to HS.ConclusionWe demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.

Exploring the interconnected between type 2 diabetes mellitus and nonalcoholic fatty liver disease: Genetic correlation and Mendelian randomization analysis.

Epidemiological and clinical studies have indicated a higher risk of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), implying a potentially shared genetic etiology, which is still less explored. Genetic links between T2DM and NAFLD were assessed using linkage disequilibrium score regression and pleiotropic analysis under composite null hypothesis. European GWAS data have identified shared genes, whereas SNP-level pleiotropic analysis under composite null hypothesis has explored pleiotropic loci. generalized gene-set analysis of GWAS data determines pleiotropic pathways and tissue enrichment using eQTL mapping to identify associated genes. Mendelian randomization analysis was used to investigate the causal relationship between NAFLD and T2DM. Linkage disequilibrium score regression analysis revealed a strong genetic correlation between T2DM and NAFLD, and identified 24 pleiotropic loci. These single-nucleotide polymorphisms are primarily involved in biosynthetic regulation, RNA biosynthesis, and pancreatic development. generalized gene-set analysis of GWAS data analysis revealed significant enrichment in multiple brain tissues. Gene mapping using these 3 methods led to the identification of numerous pleiotropic genes, with differences observed in liver and kidney tissues. These genes were mainly enriched in pancreas, brain, and liver tissues. The Mendelian randomization method indicated a significantly positive unidirectional causal relationship between T2DM and NAFLD. Our study identified a shared genetic structure between NAFLD and T2DM, providing new insights into the genetic pathogenesis and mechanisms of NAFLD and T2DM comorbidities.

Metalloproteins as risk factors for osteoarthritis: improving and understanding causal estimates using Mendelian randomization.

Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorders and a primary cause of pain and disability among the elderly population. Research on the relationship between metalloproteins (MPs) and OA is limited, and causality remains unclear. Our objective is to utilize Mendelian randomization (MR) to explore the possible causal relationship between MPs and OA. The data on MPs were derived from a Genome-Wide Association Study (GWAS) analysis involving 3301 samples. The GWAS data for OA were obtained from an analysis involving 462,933 European individuals. In this study, a variety of two-sample Mendelian randomization methods (two-sample MR) to evaluate the causal effect of MPs on OA, including inverse variance weighted method (IVW), MR-Egger method, weighted median method (WM), simple mode, weight mode, and Wald ratio. The primary MR analysis using the IVW method reveals a significant negative correlation between Metallothionein-1F (MT-1F), zinc finger protein 134 (ZNF134), calcium/calmodulin-dependent protein kinase type 1D (CAMK1D), and EF-hand calcium-binding domain-containing protein 14 (EFCAB14) with the occurrence of osteoarthritis (OA) (p value < 0.05). However, no causal relationship was observed in the opposite direction between these MPs and OA. Notably, even in combined models accounting for confounding factors, the negative association between these four MPs and OA remained significant. Sensitivity analysis demonstrated no evidence of horizontal pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the results. In this study, we have established a conspicuous association between four distinct MPs and OA. This discovery augments our understanding of potential avenues for the diagnosis and treatment of this condition. Key Points • The MR method was employed to assess the relationship between MPs and OA. • A total of four types of MPs have demonstrated inhibitory effects on the occurrence of OA.

Research on the academic thought of distinguished veteran doctors of traditional Chinese medicine based on Mendelian randomization: a case study of the causation between Sjögren’s syndrome and rheumatoid arthritis

Aim: This study investigated the causation between Sjögren’s syndrome (SS) and rheumatoid arthritis (RA) based on Mendelian randomization (MR), with the purpose of promoting research on the academic thought of distinguished veteran doctors of traditional Chinese medicine (TCM) via bioinformatics with information technology and providing new basis for better inheriting and carrying forward the valuable experience of a National Master of TCM, Zhizheng Lu. Methods: The causation between RA and SS in TCM was inferred from the perspective of coordination between dryness and dampness. For further assessment, MR was performed based on the summary data of genome-wide association studies (GWAS), with genetic loci closely related to SS(instrumental variables (IVs)), RA(research outcome), inverse-variance weighted (IVW) and MR-Egger regression and weighted median (WME) ( main MR methods). Heterogeneity was evaluated by Cochran Q test, pleiotropy by MR-Egger regression, and robustness by the Leave-One-Out method. Results: Except for MR-Egger, all other methods showed a clear statistical significance in the association between SS and RA (P&lt;0.05). Conclusion: This study, based on the academic thought of distinguished TCM veteran doctor and the thought “moistening dryness” of National Master of TCM, Zhizheng Lu, speculated that there may be a potential association between SS and RA. MR results demonstrated the clear genetic causation between SS and RA, and the guiding role of the academic thought of distinguished TCM veteran doctor in clinical practice genetically.

Smoking may increase the usage of antidepressant: evidence from genomic perspective analysis.

This study uses the two-sample Mendelian randomization (TSMR) method to explore the causal relationships between smoking initiation (SMKI), never smoking (NSMK), past tobacco smoking (PTSMK), and the usage of antidepressants (ATD). Single-nucleotide polymorphisms (SNPs) with genome-wide significance (P < 5E-08) related to SMKI, NSMK, and PTSMK were selected from the genome-wide association study (GWAS) database as instrumental variables (IVs). The main method, inverse variance weighted (IVW), was utilized to investigate the causal relationship. The results demonstrated a positive causal relationship between SMKI and ATD use, where SMKI leads to an increase in ATD use. Conversely, NSMK and PTSMK showed a negative causal relationship with ATD use, meaning that NSMK and PTSMK lead to a reduction in ATD use. Additionally, sensitivity analysis showed that the results of this study were robust and reliable. Using the TSMR method and from a genetic perspective, this study found that SMKI leads to an increase in ATD use, while NSMK and PTSMK reduce ATD use.

Association between air pollution and skin cutaneous melanoma: A Mendelian randomization study.

There has been a consistent and notable increase in the global prevalence of skin cutaneous melanoma (SKCM). Although genetic factors are closely associated with the occurrence and development of melanoma, the potential influence of environmental factors cannot be overlooked. The existing literature lacks a definitive consensus on the correlation between air pollution and the incidence rate of SKCM. This study seeks to investigate the causal relationship between air pollution, specifically focusing on particulate matter (PM) 2.5, PM2.5-10, PM10, and nitrogen oxides, and the risk of SKCM. A 2-sample Mendelian randomization (MR) method was applied, utilizing extensive publicly accessible genome-wide association studies summary datasets within European populations. The primary analytical method employed was the inverse variance weighted method. Supplementary methods, including the weighted median model, MR-Egger, simple model, and weighted model, were chosen to ensure robust analysis. Heterogeneity assessment was conducted using Cochran's Q test. To identify potential pleiotropy, both MR-Egger regression and the MR-PRESSO global test were employed. Additionally, a sensitivity analysis was performed using the leave-one-out method. The analysis revealed no statistically significant association between air pollution and SKCM risk, with specific findings as follows: PM2.5 (P = .485), PM2.5-10 (P = .535), PM10 (P = .136), and nitrogen oxides (P = .745). While some results exhibited heterogeneity, all findings demonstrated an absence of pleiotropy. This study did not find substantive evidence supporting a causal relationship between air pollution and the risk of SKCM within European populations. The comprehensive MR analysis, encompassing various pollutants, suggests that environmental factors such as air pollution may not be significant contributors to the development of SKCM.

Critical COVID-19, Victivallaceae abundance, and celiac disease: A mediation Mendelian randomization study.

Celiac disease exhibits a higher prevalence among patients with coronavirus disease 2019. However, the potential influence of COVID-19 on celiac disease remains uncertain. Considering the significant association between gut microbiota alterations, COVID-19 and celiac disease, the two-step Mendelian randomization method was employed to investigate the genetic causality between COVID-19 and celiac disease, with gut microbiota as the potential mediators. We employed the genome-wide association study to select genetic instrumental variables associated with the exposure. Subsequently, these variables were utilized to evaluate the impact of COVID-19 on the risk of celiac disease and its potential influence on gut microbiota. Employing a two-step Mendelian randomization approach enabled the examination of potential causal relationships, encompassing: 1) the effects of COVID-19 infection, hospitalized COVID-19 and critical COVID-19 on the risk of celiac disease; 2) the influence of gut microbiota on celiac disease; and 3) the mediating impact of the gut microbiota between COVID-19 and the risk of celiac disease. Our findings revealed a significant association between critical COVID-19 and an elevated risk of celiac disease (inverse variance weighted [IVW]: P = 0.035). Furthermore, we observed an inverse correlation between critical COVID-19 and the abundance of Victivallaceae (IVW: P = 0.045). Notably, an increased Victivallaceae abundance exhibits a protective effect against the risk of celiac disease (IVW: P = 0.016). In conclusion, our analysis provides genetic evidence supporting the causal connection between critical COVID-19 and lower Victivallaceae abundance, thereby increasing the risk of celiac disease.

Associations of dietary factors with gastric cancer risk: insights from NHANES 2003-2016 and mendelian randomization analyses.

Background: Gastric cancer (GC) continues to be one of the leading causes of cancer-related deaths globally. Diet significantly influences the incidence and progression of GC. However, the relationship between dietary intake and GC is inconsistent. Methods: A study was conducted with adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016 to investigate possible associations between 32 dietary factors and GC. To further detect potential causal relationships between these dietary factors and the risk of GC, a two-sample Mendelian randomization (MR) analysis was conducted. The primary method employed was the inverse variance weighted (IVW) analysis, and its results were further validated by four other methods. Results: Of the 35,098 participants surveyed, 20 had a history of GC. Based on the results of weighted logistic multivariate analysis, it was observed that there was a positive correlation between total fat intake [odds ratio (OR) = 1.09, 95% confidence interval (CI): (1.01-1.17), p = 0.03] and GC as well as negative association of dietary monounsaturated fatty acids (MUFAs) intake [OR = 0.83, 95% CI: (0.76-0.92), p < 0.001]. Further evaluations of the odds of GC across the quartiles of dietary MUFAs showed that the top quartile of total MUFA intake was associated with a lower likelihood of GC in three different models [model1: OR = 0.03, 95% CI: (0.00-0.25), p < 0.01; model2: OR = 0.04, 95% CI: (0.00-0.38), p = 0.01; model3: OR = 0.04, 95% CI: (0.00-0.40), p = 0.01]. For the MR analyses, genetic instruments were selected from the IEU Open GWAS project; IVW analysis showed that GC risk was not associated with MUFAs [OR = 0.82, 95% CI: (0.59-1.14), p = 0.23] or the ratio of MUFAs to total fatty acids [OR = 1.00, 95% CI: (0.75-1.35), p = 0.98]. Similar results were observed when using the other MR methods. Conclusion: The NHANES study revealed that consuming MUFAs was linked to a lower risk of GC, although the results of MR analyses do not provide evidence of a causal relationship. Additional research is therefore necessary to clarify these findings.

The possible causal relationship between COVID-19 and imaging markers of cerebral small vessel disease: a Mendelian randomization study

ABSTRACT Objectives Observational studies have suggested that SARS-CoV-2 infection may increase the burden of cerebral small vessel disease (CSVD). This study aims to explore the causal correlation between COVID-19 and the imaging markers of CSVD using Mendelian randomization (MR) methods. Methods Summary-level genome-wide association study (GWAS) statistics for COVID-19 susceptibility, hospitalization, and severity were utilized as proxies for exposure. Large-scale meta-analysis GWAS data on three neuroimaging markers of white matter hyperintensity, lacunar stroke, and brain microbleeds, were employed as outcomes. Our primary MR analysis employed the inverse variance weighted (IVW) approach, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. We also conducted multivariable MR analysis to address confounding bias and validate the robustness of the established causal estimates. Comprehensive sensitivity analyses included Cochran’s Q test, Egger-intercept analysis, MR-PRESSO, and leave-one-out analysis. Results The MR analysis revealed a significant causal correlation between the severity of COVID-19 and an increased risk of lacunar stroke, as demonstrated by the IVW method (ORivw = 1.08, 95% CI: 1.03–1.16, pivw = 0.005, FDR = 0.047). Nevertheless, no causal correlations were observed between COVID-19 susceptibility or hospitalization and any CSVD imaging markers. The robustness and stability of these findings were further confirmed by multivariable MR analysis and comprehensive sensitivity analyses. Discussion This study provides compelling evidence of a potential causal effect of severe COVID-19 on the incidence of lacunar stroke, which may bring fresh insights into the understanding of the comorbidity between COVID-19 and CSVD.

Dietary factors and Alzheimer’s disease risk: a Mendelian randomization study

BackgroundPrior observational research has investigated the association between dietary patterns and Alzheimer’s disease (AD) risk. Nevertheless, due to constraints in past observational studies, establishing a causal link between dietary habits and AD remains challenging.MethodsMethodology involved the utilization of extensive cohorts sourced from publicly accessible genome-wide association study (GWAS) datasets of European descent for conducting Mendelian randomization (MR) analyses. The principal analytical technique utilized was the inverse-variance weighted (IVW) method.ResultsThe MR analysis conducted in this study found no statistically significant causal association between 20 dietary habits and the risk of AD (All p > 0.05). These results were consistent across various MR methods employed, including MR-Egger, weighted median, simple mode, and weighted mode approaches. Moreover, there was no evidence of horizontal pleiotropy detected (All p > 0.05).ConclusionIn this MR analysis, our finding did not provide evidence to support the causal genetic relationships between dietary habits and AD risk.

A study on the relationship between cheese intake and caries occurrence based on Mendelian randomization method

ObjectiveThe study aims to investigate the causal relationship between cheese intake and caries occurrence by a two-sample Mendelian randomization method (TSMR). MethodsData from a genome-wide association study (GWAS) on cheese intake as an exposure factor were collected, and dental caries was the outcome variable, appropriate SNPs were selected as instrumental variables (IVs). The TSMR was analyzed by the inverse variance weighting (IVW) method, weighted median method, MR-Egger regression method, simple model and weighted model. ResultsWe identified forty-four single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (cheese) that were associated with cheese intake, and IVW was adopted. The IVW method supported a relationship between cheese intake and the risk of dental caries occurrence[OR,1.00(95%CI,0.99∼1.00), P=0.039<0.05]. There was no horizontal pleiotropy between the IVs(b=-0.0037, P=0.39), and the sensitivity analysis using the "leave-one-out" method was robust to causal effects. ConclusionThe results of the TSMR analysis supported that an appropriate intake of cheese could reduce the occurrence of dental caries.

Association between migraine and venous thromboembolism: a Mendelian randomization and genetic correlation study.

Previous observational studies have reported an increased risk of venous thromboembolism (VTE) among individuals with migraine. This study aimed to investigate the causal effect of migraine on the development of VTE, as well as explore the genetic correlation between them. We conducted a two-sample Mendelian randomization (MR) study using publicly available summary statistics from large-scale genome-wide association studies for migraine and VTE. Linkage disequilibrium score regression analysis was performed to estimate the genetic correlation between migraine and VTE. There were several shared risk variants (p-value < 5 × 10-8) between migraine and VTE. Linkage disequilibrium score regression analysis found a significant positive genetic correlation between migraine and VTE. The genetic correlations based on two migraine datasets were 0.208 (se = 0.031, p-value = 2.91 × 10-11) and 0.264 (se = 0.040, p-value = 4.82 × 10-11), respectively. Although main MR analysis showed that migraine was associated with an increased risk of VTE (odds ratio = 1.069, 95% confidence interval = 1.022-1.118, p-value = 0.004), the association attenuated to non-significance when using several other MR methods and using another set of genetic instruments. In addition, evidence of heterogeneity was found. Reverse MR analysis showed VTE was associated with increased risk of migraine with aura (odds ratio = 1.137, 95% confidence interval = 1.062-1.218, p-value = 2.47 × 10-4) with no evidence of pleiotropy and heterogeneity. We showed suggestive evidence indicating an association between migraine and increased risk of VTE. Additionally, we found robust evidence suggesting that VTE is associated with an increased risk of migraine. The positive genetic correlation indicates that migraine and VTE has shared genetic basis. Further investigations will be necessary to address potential sex-specific effects in the analysis.

Association Between Sleep Apnea Syndrome and Osteoarthritis: Insights from Bidirectional Mendelian Randomization and Bioinformatics Analysis.

Sleep apnea syndrome(SAS) and osteoarthritis (OA) are two prevalent diseases that often coexist, but the causal relationship between them remains unclear. In light of this, our team utilizes Mendelian Randomization and bioinformatics analysis methods to investigate the potential association between the two diseases. In this study, we utilized GWAS data pertaining to SAS and OA to assess the causal relationship between the two diseases through Mendelian randomization (MR) analysis. We then employed transcriptomic data to perform differential gene identification, WGCNA, shared gene determination, functional enrichment analysis, and colocalization analysis, all designed to further elucidate the mechanisms underlying the association between the two diseases. In the end, we utilized Mendelian randomization (MR) analysis again to delve deeper into the relationship between the two diseases and immune cells. Our research findings indicate that SAS is a risk factor for OA (p = 0.000004), knee OA (p = 0.0000001) and hip OA(p = 0.001). Furthermore, OA (p = 0.000195), knee OA (p = 0.001) are significant risk factors for SAS. However, there is no clear evidence that hip OA (p = 0.892) is a risk factor for SAS. Interestingly, the genes shared between OA and SAS are significantly enriched in leukocyte migration, leukocyte chemotaxis. Moreover, colocalization analysis suggests that the genes JUNB, COL8A1, FOSB, and IER2 may be key genes associated with both diseases. Furthermore, 57 immune cell phenotypes are associated with SAS, 95 with OA, and 6 shared between both diseases. This research confirmed the bidirectional causal relationship between SAS and OA. Notably, the 4 genes (JUNB, COL8A1, FOSB, IER2) and 6 immune phenotypes are crucial for both diseases, these provide hopeful targets for future interventions against these two diseases.

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study.

Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS. We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results. The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results. Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC.

Causal relationships between serum albumin, neuroticism and suicidal ideation in depressed patients: A Mendelian randomization study

Although serum albumin and neuroticism have revealed a strong association with suicidal ideation in individuals with depression, the causal relationship between them is uncertain. This study analyzed the causal association of serum albumin, neuroticism and suicidal ideation using large-scale GWAS data and Univariable Mendelian Randomization (UVMR) methods. The Multivariable MR (MVMR) analysis was used to explore the causal pathways. UVMR analysis revealed that genetically determined serum albumin is causally associated with neuroticism (β = −0.006 S.D.; 95 % CI: 0.009, −0.002; p = 0.003) and suicidal ideation (β = 0.009 S.D.; 95 % CI: 0.001, 0.016; p = 0.037); and that neuroticism mediates 100 % of the causal association between serum albumin and suicidal ideation in individuals with depression. These findings suggest genetic evidence for the causal effect of serum albumin on suicidal ideation in depressed patients and the significant mediation effect of neuroticism on this causal association. This study proves the protective role of serum albumin for neuroticism and the riskiness of personality traits for suicidal ideation in individuals with depression.

Differential ischemic stroke risk linked to novel subtypes of type 2 diabetes: insights from a Mendelian randomization analysis.

This study employs a two-sample Mendelian randomization (MR) approach to investigate the variation in ischemic stroke risk across novel subtypes of adult-onset type 2 diabetes. Leveraging pooled genome-wide association study (GWAS) data from the Swedish ANDIS cohort, we explored the association of four newly identified type 2 diabetes subtypes-severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD)-with ischemic stroke risk. The outcome data for ischemic stroke and its three subtypes (large artery, cardioembolic, and small vessel stroke) were sourced from the MEGASTROKE Consortium. Our analysis applied multiple MR methods, focusing on the inverse-variance weighted (IVW) technique, complemented by thorough sensitivity analyses to examine heterogeneity and potential horizontal pleiotropy. Our findings reveal a significant causal relationship between the SIDD subtype and small vessel stroke (OR = 1.06, 95% CI: 1.01-1.11, p = 0.025), while no causal associations were observed for SIRD with any stroke subtype. MOD was causally linked to small vessel stroke (OR = 1.07, 95% CI: 1.02-1.12, p = 0.004) and large artery stroke (OR = 1.07, 95% CI: 1.01-1.13, p = 0.015). Similarly, MARD showed a causal relationship with small vessel stroke (OR = 1.09, 95% CI: 1.03-1.16, p = 0.006) and overall ischemic stroke risk (OR = 1.04, 95% CI: 1.01-1.08, p = 0.010). Our study highlights distinct causal links between specific type 2 diabetes subtypes and ischemic stroke risks, emphasizing the importance of subtype-specific prevention and treatment strategies.

Eosinophils and risk of ulcerative colitis in European population: Evidence from Mendelian randomization study.

Observational studies have indicated that peripheral blood eosinophil count is elevated in individuals diagnosed with ulcerative colitis (UC) and correlates with the disease activity of UC. However, this conclusion contradicts with findings from other studies. Therefore, we employed Mendelian randomization (MR) method to assess the genetic link between eosinophil count and UC. This MR study utilized summary data from genome-wide association studies (GWAS) on eosinophil count and UC. The main approach used for conducting MR analysis was the inverse variance weighted (IVW) method. Meta-analysis of the IVW results was performed alongside multiple sensitivity analyses to confirm the robustness of the MR analysis results. The IVW method unveiled a causal relationship between eosinophil count and UC (OR = 1.18, 95% CI: 1.04-1.33, p = .01) in the discovery cohort. This finding was further corroborated by the replication cohorts (OR = 1.16, 95% CI: 1.04-1.29, p = .01; OR = 1.12, 95% CI: 1.01-1.24, p = .03). The meta-analysis indicated that the overall odds ratio (OR) for all studies was 1.15 (common effect model, 95% CI: 1.08-1.23, p < .01). Sensitivity analysis suggested the absence of heterogeneity and horizontal pleiotropy in all MR analyses. Based on bidirectional two-sample MR analysis, there is an indication that elevated eosinophil count may increase the risk of UC. However, potential confounding factors cannot be ruled out, and further research is necessary to explore how eosinophils contribute to the onset and progression of UC.