Genetic Insights Into Skin Diseases and Depression: Evidence From East Asian Mendelian Randomization Analysis

Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics between MDD and dyslipidaemia remain elusive. To comprehensively disentangle the genetic causality between MDD and various phenotypes of blood lipids, thereby facilitating the advancement of management strategies for these conditions. We conducted a two-sample univariable Mendelian randomisation (MR) analysis using different models, including the inverse variance weighted (IVW) method and causal analysis using the summary effect (CAUSE) estimates, as well as a multivariable MR analysis. This analysis used summary statistics from genome-wide association studies (GWAS) of MDD and five lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol and triglycerides (TG), encompassing 5 237 893 individuals of European and East Asian ancestries. For MDD, a total of 598 701 individuals were included, with 500 199 individuals of European ancestry (Ncase=170 756, Ncontrol=329 443) and 98 502 of East Asian ancestry (Ncase=12 588, Ncontrol=85 914). Lipid data were collected from 4 639 192 individuals through the Global Lipids Genetics Consortium (European, N=4 096 085; East Asian, N=543 107). Next, we used the two-step MR to explore the mediating factors between MDD and TG, and the risk factors affecting TG through MDD. Finally, we conducted a GWAS meta-analysis and enrichment analysis. In univariable MR, we observed a negative causal effect of low-density lipoprotein on MDD in both European populations (IVW: odds ratio (OR): 0.972, 95% confidence interval (CI) 0.947 to 0.998, p=0.037) and East Asian populations (IVW: OR: 0.928, 95% CI 0.864 to 0.997, p=0.042). Additionally, we identified a bidirectional causal relationship between TG and MDD, with TG having a causal effect on MDD (IVW: OR: 1.052, 95% CI 1.020 to 1.085, p=0.001) and MDD having a causal effect on TG (IVW: OR: 1.075, 95% CI 1.047 to 1.104, p<0.001). Multivariable MR analysis further supported the role of TG in MDD (OR: 1.205, 95% CI 1.034 to 1.405, p=0.017). CAUSE estimates indicated that the causal model of MDD on TG provided a better fit than the sharing model (p=0.003), while the association of TG on MDD was more likely due to horizontal correlated pleiotropy than causality. Mediation analyses revealed that waist-hip ratio (WHR) mediated 69% of the total causal effect of MDD on TG, while other identified risk factors exhibited lower mediating proportions either mediated through MDD (≤17%) or originating from MDD (≤29%). The GWAS meta-analysis highlighted potential pathways related to lipid processes and nucleosome assembling, with significant cell types identified in brain regions and liver tissues. The findings indicate that genetic proxies of MDD are associated with elevated levels of TG, with WHR serving as a clinical indicator of the association. This suggests that interventions targeting WHR may be effective in reducing TG levels in patients with MDD.

Lung cancer is frequently observed as a second primary malignancy following gastric cancer, yet the genetic causality between them remains uncertain. This study aims to evaluate the causal relationship between gastric and lung cancers using Mendelian randomization (MR) analysis. Single nucleotide polymorphisms associated with gastric and lung cancers were selected from Genome-Wide Association Study in East Asian and European populations as instrumental variables. The causal effects between gastric and lung cancers were evaluated using univariable and multivariable MR analysis, with the inverse variance weighted (IVW) method serving as the primary criterion. Heterogeneity and sensitivity analyses were performed to ensure the robustness of the findings. Univariable MR analysis demonstrated that genetic susceptibility to gastric cancer in the European population was significantly associated with an increased risk of lung cancer (IVW: OR:1.285, 95%CI:1.072-1.541, p=6.83E-03), which was consistently validated in the East Asian population (IVW:OR:1.356, 95% CI:1.114-1.651, p=2.40E-03). Multivariable MR analysis further indicated that the significant positive causal relationship between gastric cancer and lung cancer persisted in both populations after adjusting for confounding factors (all p<0.05). Conversely, no significant causal relationship was observed for the risk of developing gastric cancer following the diagnosis of lung cancer diagnosis in either population (p>0.05). This study confirms that genetic susceptibility to gastric cancer increases the risk of lung cancer. This finding provides a theoretical basis for exploring the underlying biological mechanisms and suggests that enhancing lung cancer screening in patients with gastric cancer may be necessary to improve patient prognosis.

Major depressive disorder (MDD) and venous thromboembolism (VTE) may be linked in observational studies. However, the causal association remains ambiguous. Therefore, this study investigates the causal associations between them. We performed a two-sample univariable and multivariable bidirectional Mendelian randomization (MR) analysis to evaluate the associations between MDD and VTE. The summary genetic associations of MDD statistics were obtained from the Psychiatric Genomics Consortium and UK Biobank. Information on VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE) were obtained from the FinnGen Biobank. Inverse-variance weighting was used as the main analysis method. Other methods include weighted median, MR-Egger, Simple mode, and Weighted mode. Univariable MR analysis revealed no significant associations between MDD and VTE risk (odds ratio (OR): 0.936, 95% confidence interval (CI): 0.736-1.190, p = 0.590); however, after adjusting the potential relevant polymorphisms of body mass index and education, the multivariable MR analysis showed suggestive evidence of association between them (OR: 1.163, 95% CI: 1.004-1.346, p = 0.044). Univariable MR analysis also revealed significant associations between MDD and PE risk (OR: 1.310, 95% CI: 1.073-1.598, p = 0.008), but the association between them was no longer significant in MVMR analysis (p = 0.072). We found no significant causal effects between MDD and DVT risk in univariable or multivariable MR analyses. There was also no clear evidence showing the causal effects between VTE, PE, or DVT and MDD risk. We provide suggestive genetic evidence to support the causal association between MDD and VTE risk. No causal associations were observed between VTE, PE, or DVT and MDD risk. Further validation of these associations and investigations of potential mechanisms are required.

It remains unclear about the pathogenesis of intracranial aneurysms (IAs) in the setting of autoimmune disorders (ADs). However, the underlying systemic inflammatory characteristics of ADs may affect IAs through shared inflammatory pathways. Therefore, this study was conducted to explore the relationship between ADs and IAs and assess causal effects. In this study, 6 common ADs were included to explore their causal relationship with IAs. Besides, a bidirectional two-sample univariable Mendelian randomization (UVMR) analysis was performed. In addition, the primary analysis was performed by the inverse variance weighted (IVW) and Bayesian weighted Mendelian randomization (BWMR) method, and a series of sensitivity analyses were performed to assess the robustness of the results. Further, the data related to ADs and IAs were collected from open genome-wide association study studies (GWASs) and the Cerebrovascular Disease Knowledge Portal (CDKP) (including 11,084 cases and 311,458 controls), respectively. These analyses were conducted based on both the East Asian and European populations. Moreover, 6 ADs were subject to grouping according to connective tissue disease, inflammatory bowel disease, and thyroid disease. On that basis, a multivariate MR (MVMR1) analysis was further performed to explore the independent causal relationship between each AD and IAs, and an MVMR 2 analysis was conducted to investigate such potential confounders as smoking, alcohol consumption, and systolic blood pressure. Finally, these results were verified based on the data from another GWAS of IAs. The UVMR analysis results demonstrated that systemic lupus erythematosus (SLE) was associated with a high risk of IAs in the East Asian population (IVW OR, 1.06; 95%CI, 1.02-1.11; p = 0.0065, UVMR), which was supported by the results of BWMR (OR, 1.06; 95%CI, 1.02-1.11; p = 0.0067, BWMR), MVMR1 (OR, 1.06; 95%CI, 1.01-1.10; p = 0.015, MVMR1), MVMR2 (OR, 1.05; 95%CI, 1.00-1.11; p = 0.049, MVMR2), and sensitivity analyses. The results in the validation group also suggested a causal relationship between SLE and IAs (IVW OR, 1.04; 95% CI, 1.00-1.09; p = 0.046). The reverse MR analysis results did not reveal a causal relationship between IAs and ADs. In this MR study, SLE was validated to be a risk factor for IAs in the East Asian population. Therefore, the management of IAs in patients with SLE should be highlighted to avoid stroke events.

BackgroundObservational studies have shown that individual sleep traits habits are potential risk factors for major depression. However, it is not known whether there is a causal relationship between individual sleep traits habits such as continuous sleep duration, short sleep duration, short sleep duration, insomnia, nap during the day, snoring, and major depression. In this study, Mendelian randomization (MR) was used to predict major depressive disorder (MDD) in individuals sleep traits habits. MethodsData were obtained from the genome-wide association study (GWAS). Nine MR analysis methods were used: Inverse Variance Weighted (IVW) [fixed effects/multiplicative random effects], simple mode, simple mode, weighted mode, simple median, weighted median, penalised weighted median, and MR-Egger, MR Egger (bootstrap). IVW was used as the main analysis method for the MR analysis of two samples, and the other methods were used as supplements. ResultsThe results obtained through the IVW method supported a causal relationship between sleep duration and decreased risk of MDD (odds ratio, ORivw: 0.998; 95 % CI: 0.996–0.999, P<0.001). Two-Sample MR, results showed that short sleep duration has a causal effect on the increased risk of MDD (odds ratio, ORivw: 1.179; 95 % CI: 1.108–1.255, P<0.001). However, there were no sufficient evidence supported that long sleep duration has a causal effect on the decreased risk of MDD (odds ratio, ORivw: 0.991; 95 % CI: 0.924–1.062, P = 0.793). A significant causal relationship between insomnia and increased risk of MDD was observed (OR: 1.233; 95 % CI: 1.214–1.253, P<0.001). Interestingly, our study also found that daytime napping has a causal effect on the increased risk of MDD (odds ratio, ORivw: 1.519; 95 % CI: 1.376–1.678, P<0.001). The present results did not show a significant causal relationship between snoring and the risk of MDD (ORivw: 1.000; 95 % CI: 0.998–1.002, P = 0.906). Obstructive sleep apnea (odds ratio, ORivw: 1.021; 95 % CI: 0.972–1.072, P = 0.407) and morning person (odds ratio, ORivw: 1.021; 95 % CI: 0.972–1.072, P = 0.407) have no causal effect on the increased risk of MDD. LimitationsThe study could not ascertain whether there were genetic differences among different ethnicities, nations, and regions, as it only included participants of European ancestry. ConclusionsIn summary, our research provides genetic evidence for the relationship between individual sleep traits (short sleep duration, insomnia, daytime napping) and the increased risk of MDD. Interventions targeting lifestyle factors may reduce the risk of MDD.

Associations between type 1 diabetes and autoimmune skin diseases: Mendelian randomization analysis

Genetically predicted processed meat, red meat intake, and risk of mental disorders: A multivariable Mendelian randomization analysis

This study aims to analyze the causal relationship between Proton Pump Inhibitors (PPI) and the risk of Dementia (DEM) using Mendelian Randomization (MR) analysis, providing a reference for clinical medication decisions. Based on summary data from Genome-Wide Association Studies (GWAS), this study uses two common PPI drugs, Lansoprazole (LAN) and Omeprazole (OME), as exposure factors. DEM and its five subtypes: Dementia in Alzheimer Disease (DAD), Vascular Dementia (VD), Dementia due to Parkinson Disease (DPD), Dementia with Lewy bodies (DLB), and Frontotemporal Dementia (FTD) are used as outcome factors. The main method used to assess causal relationships is the Inverse Variance Weighted (IVW) method; other MR methods and sensitivity analyses are also conducted as supplements. There is a significant positive causal relationship between LAN and DEM (IVW: OR = 1.29E + 05, 95% CI: 1.60E + 00 to 1.04E + 10; P = 0.041), and DAD (IVW: OR = 2.39E + 04, 95% CI: 1.09E + 00 to 5.23E + 08; P = 0.048); no significant causal relationship was found between LAN and VD, DPD, DLB, FTD (P > 0.05). There is a significant positive causal relationship between OME and FTD (IVW: OR = 2.95E + 11, 95% CI: 2.13E + 02 to 4.09E + 20; P = 0.014), and a significant negative causal relationship with VD (IVW: OR = 9.56E-07, 95% CI: 1.69E-12 to 5.40E-01; P = 0.040); no significant causal relationship was found between OME and DEM, DAD, DPD, DLB (P > 0.05). This study reveals that LAN may increase the risk of DEM and DAD; OME may increase the risk of FTD and may reduce the risk of VD. This provides a reference for the rational clinical use of PPI.

BackgroundInflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have been inconsistent and may face the bias of confounding and reverse causality. The potential causal relationships between IBD and the risk of cancers remain largely unclear.MethodsWe performed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analyses using summary genome-wide association study (GWAS) data across East Asian and European populations to evaluate the causal relationships between IBD and cancers. Sensitivity analyses for the MR approach were additionally performed to explore the stability of the results.ResultsThere were no significant genetic correlations between IBD, CD, or UC and cancers (all P values > 0.05) in East Asian or European populations. According to the main MR analysis, no significant causal relationship was observed between IBD and cancers in the East Asian population. There were significant associations between CD and ovarian cancer (odds ratio [OR] = 0.898, 95% CI = 0.844–0.955) and between UC and nonmelanoma skin cancer (OR = 1.002, 95% CI = 1.000–1.004, P = 0.019) in the European population. The multivariable MR analysis did not find any of the above significant associations. There was no shared causal variant to prove the associations of IBD, CD, or UC with cancers in East Asian or European populations using colocalization analysis.ConclusionsWe did not provide robust genetic evidence of causal associations between IBD and cancer risk. Exposure to IBD might not independently contribute to the risk of cancers, and the increased risk of cancers observed in observational studies might be attributed to factors accompanying the diagnosis of IBD.

Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis. We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results. We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P = 0.002). The statistical powers of positive MR results were all >0.9. This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.

Mendelian randomization analysis of atopic dermatitis and esophageal cancer in East Asian and European populations

Mediating effects of gastroesophageal reflux disease and smoking behavior on the relationship between depression and chronic obstructive pulmonary disease: Trans-ethnic Mendelian randomization study.

The previous observational studies could not overcome the effects of confounding variables and reverse causality. We aimed to determine whether there is a causal relationship between systemic lupus erythematosus and osteoporosis in East Asian and European populations, respectively, by two-sample Mendelian Randomization analysis. We obtained and downloaded data from publicly available genome-wide association study databases and analyses for East Asian and European populations, including systemic lupus erythematosus (SLE), osteoporosis (OP), multisite bone mineral density (BMD), and OP with fracture. After screening for instrumental single-nucleotide polymorphisms (SNPs) significantly correlated to SLE, the inverse-variance weighted (IVW) method was used for calculating the ratio and 95% confidence interval, besides utilizing MR-Egger, weighted median, and weighted mode to assess the robustness of the primary outcome. Moreover, multiple analyses, including MR-PRESSO, MR-Egger intercept, Cochran's Q test, as well as "leave-one-out" sensitivity, were used for evaluating horizontal pleiotropy, heterogeneity, and stability. Finally, we exchanged exposure and outcome and performed a reverse MR analysis. IVW (OR = 1.05, 95% CI = 1.01-1.09, P = 0.009) indicated a significant positive correlation between genetically predicted SLE and OP in East Asians. Furthermore, neither heterogeneity nor horizontal pleiotropy was observed. In Europe, there was no significant genetically predicted causal relation between SLE and OP. Bi-directional MR analysis showed no reverse causality between SLE and OP. In the East Asian population, genetically predicted SLE may have had a positive causal relationship with OP. In Europe, there is insufficient evidence for a potential causal relation between SLE and OP or BMD and fracture, and the correlations currently observed may be attributed to a variety of confounder variables.

Genetic evidence suggests a genetic association between major depressive disorder and reduced cortical gray matter volume: A Mendelian randomization study and mediation analysis

BackgroundUlcerative colitis (UC) was positively related to atopic dermatitis (AD) in previous observational studies, but the causal relationship is unclear. We aimed to explore the potential causal correlation between UC...