Two-sample Mendelian Randomization Study Research Articles

Association Between Neuroinflammation and Parkinson's Disease: A Comprehensive Mendelian Randomization Study.

The objective of the study is to determine the causal relationship and potential mechanisms between Parkinson's disease (PD) and neuroinflammatory and neurotoxic mediators. We conducted two-sample Mendelian randomization (2SMR) study and multivariable Mendelian randomization (MVMR) analysis to investigate the causality between PD and neuroinflammatory and neurotoxic mediators. The mediation analysis with MR was also conducted to determine the potential mediating effect of neuroinflammatory and neurotoxic mediators between asthma and PD. Genetically predicted levels of nine neuroinflammation were associated with changes in PD risk. The associations of PD with CCL24, galectin-3 levels, haptoglobin, and Holo-Transcobalamin-2 remained significant in multivariable analyses. The mediation analysis with MR revealed that asthma affects PD through CCL24 and galectin-3. The results showed neuroinflammation could affect the pathogenesis of PD. In the combined analysis of these nine variables, CCL24, galectin-3 levels, HP, and Holo-Transcobalamin-2 alone were found to be significant. Asthma plays an intermediary role through CCL24 and galectin-3 levels.

Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study

BackgroundThe intricate etiology of autoimmune liver disease (AILD) involves genetic, environmental, and other factors that yet to be completely elucidated. This study comprehensively assessed the causal association between genetically predicted modifiable risk factors and AILD by employing Mendelian randomization.MethodsGenetic variants associated with 29 exposure factors were obtained from genome-wide association studies (GWAS). Genetic association data with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were also obtained from publicly available GWAS. Univariate and multivariate Mendelian randomization analyses were performed to identify potential risk factors for AILD.ResultsGenetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423–1.843, P = 2.506 × 10− 13) was significantly associated with an increased risk of AIH. Genetically predicted smoking initiation (OR = 1.637, 95%CI 1.055–2.540, P = 0.028), lower coffee intake (OR = 0.359, 95%CI 0.131–0.985, P = 0.047), cholelithiasis (OR = 1.134, 95%CI 1.023–1.257, P = 0.017) and higher C-reactive protein (CRP) (OR = 1.397, 95%CI 1.094–1.784, P = 0.007) were suggestively associated with an increased risk of AIH. Genetically predicted inflammatory bowel disease (IBD) (OR = 1.212, 95%CI 1.127–1.303, P = 2.015 × 10− 7) and RA (OR = 1.417, 95%CI 1.193–1.683, P = 7.193 × 10− 5) were significantly associated with increased risk of PBC. Genetically predicted smoking initiation (OR = 1.167, 95%CI 1.005–1.355, P = 0.043), systemic lupus erythematosus (SLE) (OR = 1.086, 95%CI 1.017–1.160, P = 0.014) and higher CRP (OR = 1.199, 95%CI 1.019–1.410, P = 0.028) were suggestively associated with an increased risk of PBC. Higher vitamin D3 (OR = 0.741, 95%CI 0.560–0.980, P = 0.036) and calcium (OR = 0.834, 95%CI 0.699–0.995, P = 0.044) levels were suggestive protective factors for PBC. Genetically predicted smoking initiation (OR = 0.630, 95%CI 0.462–0.860, P = 0.004) was suggestively associated with a decreased risk of PSC. Genetically predicted IBD (OR = 1.252, 95%CI 1.164–1.346, P = 1.394 × 10− 9), RA (OR = 1.543, 95%CI 1.279–1.861, P = 5.728 × 10− 6) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141–0.510, P = 6.172 × 10− 5) were positively associated with an increased risk of PSC.ConclusionsEvidence on the causal relationship between 29 genetically predicted modifiable risk factors and the risk of AIH, PBC, and PSC is provided by this study. These findings provide fresh perspectives on the management and prevention strategies for AILD.

Plasma fatty acids and attention deficit hyperactivity disorder: a Mendelian randomization investigation

BackgroundAttention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood, and pathogenesis is not fully understood. Observational studies suggest an association between fatty acids abnormalities and ADHD, but there are contradictions and differences between these findings. To address this uncertainty, we employed a two-sample bidirectional Mendelian Randomization (MR) analysis to investigate the causal relationship between fatty acids and ADHD.MethodsWe conducted a two-sample Mendelian Randomization (MR) study, selecting single nucleotide polymorphisms (SNPs) highly correlated with fatty acid levels from the CHARGE Consortium as our instruments. The outcome data were sourced from the Psychiatric Genomics Consortium (PGC) dataset on ADHD, comprising 225,534 individuals, with 162,384 cases and 65,693 controls. Inverse variance weighting, MR-Egger, and weighted median methods were employed to estimate the causal relationship between fatty acids and ADHD. Cochran’s Q-test was used to quantify heterogeneity of instrumental variables. Sensitivity analyses included MR-Egger intercept tests, leave-one-out analyses, and funnel plots.ResultsThe MR analysis revealed no significant associations between genetically predicted levels of various saturated, monounsaturated, and polyunsaturated fatty acids (including omega-3 and omega-6) and ADHD risk in the CHARGE and PGC cohorts. Notably, an initial association with Dihomo-gamma-linolenic acid (DGLA) (OR = 1.009, p = 0.032 by IVW) did not persist after correction for multiple testing (adjusted p-value = 0.286). Sensitivity analysis supported our findings, indicating robustness. Moreover, there was a lack of evidence supporting a causal link from ADHD to fatty acids.ConclusionWhile our study on the basis of genetic data does not provide evidence to support the causal role of fatty acids in ADHD, it does not preclude their potential involvement in reducing the risk of ADHD. Further research is needed to explore this possibility.

Educational attainment and psychiatric diagnoses: a national registry data and two-sample Mendelian randomization study

Educational attainment and psychiatric diagnoses: a national registry data and two-sample Mendelian randomization study

No genetic causal association between periodontitis and ankylosing spondylitis: a bidirectional two-sample mendelian randomization analysis

BackgroundObservational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse causality and confounding factors, which make it challenging to infer cause-and-effect relationships. We conducted a two-sample Mendelian randomization (MR) study to examine the causal relationship between the genetic prediction of PD and AS.MethodsIn our study, single-nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs). The genetic association with PD came from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium, wherein 17353 cases of European ancestry and 28210 controls of European ancestry were included in this study. The genetic association with AS from the Neale Laboratory Consortium included 337,159 individuals from the United Kingdom, with 968 cases and 336,191 controls. MR analysis was mainly performed using the inverse-variance weighted (IVW) method. In addition, the robustness of the study findings was assessed using sensitivity, pleiotropy, and heterogeneity analyses.ResultsEighteen independent SNPs with P-values significantly smaller than 1 × 10− 5 were used as IV SNPs for PD, while 39 independent SNPs with P-values significantly smaller than 1 × 10− 5 were used as IV SNPs for AS. The results of the IVW method revealed no causal association between PD and AS (odds ratio = 1.00, 95% confidence interval: 0.99953 to 1.00067, P = 0.72). The MR-Egger method did not support the causal association between PD and AS. It is unlikely that horizontal pleiotropy distorts causal estimates based on sensitivity analysis. No significant heterogeneity was observed in the Q test. The ‘’leave-one-out’’ analysis demonstrated that the robustness of our results was unaffected by eliminating any of the IVs. Likewise, no significant causative effect for AS on PD was observed in the inverse MR analysis.ConclusionsThe study results do not support shared heritability or a causal association between PD and AS.

Causal relationships between blood metabolites and diabetic retinopathy: a two-sample Mendelian randomization study

BackgroundDiabetic retinopathy (DR) is a microvascular complication of diabetes, severely affecting patients’ vision and even leading to blindness. The development of DR is influenced by metabolic disturbance and genetic factors, including gene polymorphisms. The research aimed to uncover the causal relationships between blood metabolites and DR.MethodsThe two-sample mendelian randomization (MR) analysis was employed to estimate the causality of blood metabolites on DR. The genetic variables for exposure were obtained from the genome-wide association study (GWAS) dataset of 486 blood metabolites, while the genetic predictors for outcomes including all-stage DR (All DR), non-proliferative DR (NPDR) and proliferative DR (PDR) were derived from the FinnGen database. The primary analysis employed inverse variance weighted (IVW) method, and supplementary analyses were performed using MR-Egger, weighted median (WM), simple mode and weighted mode methods. Additionally, MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis were also conducted to guarantee the accuracy and robustness of the results. Subsequently, we replicated the MR analysis using three additional datasets from the FinnGen database and conducted a meta-analysis to determine blood metabolites associated with DR. Finally, reverse MR analysis and metabolic pathway analysis were performed.ResultsThe study identified 13 blood metabolites associated with All DR, 9 blood metabolites associated with NPDR and 12 blood metabolites associated with PDR. In summary, a total of 21 blood metabolites were identified as having potential causal relationships with DR. Additionally, we identified 4 metabolic pathways that are related to DR.ConclusionThe research revealed a number of blood metabolites and metabolic pathways that are causally associated with DR, which holds significant importance for screening and prevention of DR. However, it is noteworthy that these causal relationships should be validated in larger cohorts and experiments.

The causal association of cheese intake with type 2 diabetes mellitus result from a two-sample Mendelian randomization study

IntroductionWorldwide, type 2 diabetes is a major health concern with numerous risk factors. In observational studies, cheese consumption has been linked to type 2 diabetes, however it is still unclear whether these relationships are causal. To ascertain these relationships, we performed a two-sample Mendelian randomization (MR) study.Material and methodsA summary of cheese intake statistics from UK Biobank and publicly available genome-wide association studies (GWAS) for type 2 diabetes from IEU OpenGWAS, FinnGen Biobank, EBI GWAS, and Biobank Japan, respectivel. The primary method was pooled meta-analysis with the inverse variance weighting method. The sensitivity analyses included MR-Egger regression, weighted median, weighted mode, and leave-one-out. MR estimations of causation were reported as odds ratios (OR) with 95% confidence intervals (CI).ResultsIn the pooled meta-analysis of the fixed and random effect model, the combined ORs for type 2 diabetes were 0.58 (95% CI: 0.50-0.68, P<0.001) and 0.50 (95%CI: 0.32-0.78, P=0.003) per standard deviation rise in the levels of cheese intake. Sensitivity analysis revealed no horizontal pleiotropy (all P>0.05) but heterogeneity (all P<0.05).ConclusionsWe found that moderate consumption of beneficial cheese may reduce the risk of type 2 diabetes. These findings suggested that increasing cheese intake appropriate for humans may help prevent and control type 2 diabetes.

Relationship between plasma brain-derived neurotrophic factor levels and neurological disorders: an investigation using Mendelian randomisation

BackgroundAltered brain-derived neurotrophic factor (BDNF) concentrations have been detected in the central nervous system tissues and peripheral blood. These alterations are associated with a series of neurological disorders. ObjectiveTo investigate the potential causal relationships between genetically determined plasma BDNF levels and various neurological diseases using a two-sample Mendelian randomisation study. MethodsWe selected single nucleotide polymorphisms strongly related to plasma BDNF levels as instrumental variables. Within the Mendelian randomisation framework, we used summary-level statistics for exposure (plasma BDNF levels) and outcomes (neurological disorders). ResultsWe observed suggestive evidence of a relation between higher plasma BDNF levels and less risk of nontraumatic intracranial haemorrhage (nITH) (odds ratio [OR] = 0.861, 95% confidence interval [CI]: 0.774-0.958, P = 0.006, PFDR = 0.078), epilepsy (OR = 0.927, 95% CI: 0.880-0.976, P = 0.004, PFDR = 0.078), focal epilepsy (OR = 0.928, 95% CI: 0.874–0.986, P = 0.016, PFDR = 0.139), and non-lesional focal epilepsy (OR = 0.981, 95% CI: 0.964–0.999, P = 0.041, PFDR = 0.267). Combined with the UK Biobank dataset, the association of plasma BDNF levels with nITH remained significant (OR = 0.88, 95% CI: 0.81-0.96, P < 0.01). The combined analysis of three consortium datasets demonstrated a considerable impact of plasma BDNF on epilepsy (OR = 0.94, 95% CI: 0.90-0.98, P < 0.01) and a suggestive impact on focal epilepsy (OR = 0.94, 95% CI: 0.89-0.99, P = 0.02). However, there was no apparent correlation between plasma BDNF levels and other neurological disorders or related subtypes. ConclusionsOur study supports a possible causal relationship between elevated plasma BDNF levels and a reduced risk of nITH, epilepsy, and focal epilepsy.

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

ObjectivePrevious 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.MethodsWe 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.ResultsThere were several shared risk variants (p-value &amp;lt; 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.ConclusionWe 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.

Causal associations between gut microbiota and synovitis–tenosynovitis: a two-sample Mendelian randomization study

BackgroundIncreasing evidence indicates that gut microbiota dysbiosis is related to synovitis and tenosynovitis. Nonetheless, whether these associations are causal is currently unknown.ObjectivesA two-sample Mendelian randomization (MR) study was performed to reveal the causality of gut microbiota with synovitis and tenosynovitis.MethodsThe summary statistical data from a large-scale genome-wide association study (GWAS) were applied as the basis for a two-sample MR analysis. The causal effect was estimated using inverse variance weighted (IVW), weighted median, simple mode, MR-Egger, and weighted mode methods, of which IVW was the important method. Meanwhile, the pleiotropy and heterogeneity were detected and measured using MR-Egger regression, Cochran’s Q statistics, funnel plots, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.ResultsThe IVW technique demonstrated that genetically predicted five genera, namely Gordonibacter [odds ratio (OR) = 0.999, 95% confidence interval (CI): (0.9977, 0.9998), p = 0.019], Paraprevotella [OR = 0.999, 95% CI: (0.9971, 0.9999), p = 0.036], Lachnoclostridium [OR = 0.998, 95% CI: (0.9954, 0.9999), p = 0.041], RuminococcaceaeUCG003 [OR = 0.997, 95% CI: (0.9955, 0.9994), p = 0.011], and FamilyXIIIAD3011group [OR = 0.997, 95% CI: (0.9954, 0.9992), p = 0.006] were negatively correlated with the risk of synovitis and tenosynovitis, while two other genera, namely Ruminococcustorquesgroup [OR = 1.003, 95% CI: (1.0004, 1.0049), p = 0.019] and Parabacteroides [OR = 1.003, 95% CI: (1.0002, 1.0052), p = 0.035] were positively associated with synovitis and tenosynovitis risk. In addition, the data of sensitivity analyses demonstrated that there were no outliers, horizontal pleiotropy, or heterogeneity in the causal relationship of the above-mentioned gut microbiota on synovitis and tenosynovitis (p &amp;gt; 0.05).ConclusionThe results of the study suggested that the gut microbiota was causally involved in synovitis and tenosynovitis and identified specific bacterial taxa that affect synovitis and tenosynovitis, which provide new insights into the pathogenesis underlying the development of synovitis and tenosynovitis mediated by gut microbiota.

​Comprehensive mendelian randomization analysis of plasma proteomics to identify new therapeutic targets for the treatment of coronary heart disease and myocardial infarction.

Ischemic heart disease is one of the leading causes of mortality worldwide, and thus calls for development of more effective therapeutic strategies. This study aimed to identify potential therapeutic targets for coronary heart disease (CHD) and myocardial infarction (MI) by investigating the causal relationship between plasma proteins and these conditions. A two-sample Mendelian randomization (MR) study was performed to evaluate more than 1600 plasma proteins for their causal associations with CHD and MI. The MR findings were further confirmed through Bayesian colocalization, Summary-data-based Mendelian Randomization (SMR), and Transcriptome-Wide Association Studies (TWAS) analyses. Further analyses, including enrichment analysis, single-cell analysis, MR analysis of cardiovascular risk factors, phenome-wide Mendelian Randomization (Phe-MR), and protein-protein interaction (PPI) network construction were conducted to verify the roles of selected causal proteins. Thirteen proteins were causally associated with CHD, seven of which were also causal for MI. Among them, FES and PCSK9 were causal proteins for both diseases as determined by several analytical methods. PCSK9 was a risk factor of CHD (OR = 1.25, 95% CI: 1.13-1.38, P = 7.47E-06) and MI (OR = 1.36, 95% CI: 1.21-1.54, P = 2.30E-07), whereas FES was protective against CHD (OR = 0.68, 95% CI: 0.59-0.79, P = 6.40E-07) and MI (OR = 0.65, 95% CI: 0.54-0.77, P = 5.38E-07). Further validation through enrichment and single-cell analysis confirmed the causal effects of these proteins. Moreover, MR analysis of cardiovascular risk factors, Phe-MR, and PPI network provided insights into the potential drug development based on the proteins. This study investigated the causal pathways associated with CHD and MI, highlighting the protective and risk roles of FES and PCSK9, respectively. FES. Specifically, the results showed that these proteins are promising therapeutic targets for future drug development.

Causal relationship between intervertebral disc degeneration and osteoporosis: a bidirectional two-sample Mendelian randomization study

IntroductionThe relationship between intervertebral disc degeneration (IVDD) and osteoporosis (OP), diagnosed primarily using bone mineral density (BMD), remains unclear so far. The present study, therefore, aimed to investigate the potential relationship between osteoporosis and intervertebral disc degeneration using Mendelian randomization and genome-wide association analyses. Specifically, the impact of bone mineral density on the development of intervertebral disc degeneration was evaluated.Materials and methodsThe genome-wide association studies (GWAS) summary data of OP/BMDs and IVDD were collected from the FinnGen consortium, the GEFOS consortium, and MRC-IEU. The relationship between IVDD and OP was then explored using TSMR. The inverse-variance weighted (IVW) method was adopted as the primary effect estimate, and the reliability and stability of the results were validated using various methods, including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO.ResultsNo significant causal relationship was observed between OP and IVDD (IVW, P &amp;gt; 0.05) or between femoral neck BMD (FA-BMD) and IVDD when OP and FA-BMD were used as exposures. However, increased levels of total body BMD (TB-BMD) and lumbar spine BMD (LS-BMD) were revealed as significant risk factors for IVDD (TB-BMD: IVW, OR = 1.201, 95% CI: 1.123–1.284, P = 8.72 × 10−8; LS-BMD: IVW, OR = 1.179, 95% CI: 1.083–1.284, P = 1.43 × 10−4). Interestingly, both heel BMD (eBMD) and femur neck BMD (FN-BMD) exhibited potential causal relationships (eBMD: IVW, OR = 1.068, 95% CI: 1.008–1.131, P = 0.0248; FN-BMD, IVW, OR = 1.161, 95% CI: 1.041–1.295, P = 0.0074) with the risk of IVDD. The reverse MR analysis revealed no statistically causal impact of IVDD on OP and the level of BMD (P &amp;gt; 0.05).ConclusionOP and the level of FA-BMD were revealed to have no causal relationship with IVDD. The increased levels of TB-BMD and LS-BMD could promote the occurrence of IVDD. Both eBMD and FN-BMD have potential causal relationships with the risk of IVDD. No significant relationship exists between IVDD and the risk of OP. Further research is warranted to comprehensively comprehend the molecular mechanisms underlying the impact of OP and BMD on IVDD and vice versa.

Understanding the Causal Relationships Between Opioid Dependence and Risk of Mental Disorders: A Comprehensive Two-Sample Mendelian Randomization Study

Understanding the Causal Relationships Between Opioid Dependence and Risk of Mental Disorders: A Comprehensive Two-Sample Mendelian Randomization Study

Causal analysis of body composition measurements in osteoarthritis knee: a two-sample mendelian randomization study

BackgroundTo analyse the causal associations of different physical measures with osteoarthritis knee (KOA).MethodsExposure factors (weight, body mass index (BMI), body fat percentage, waist circumference, hip circumference, waist–hip ratio (WHR), and basal metabolic rate (BMR)), and outcome factor KOA were analyzed by inverse-variance weighted (IVW) method, along with heterogeneity test, sensitivity and pleiotropy analyses. Meta-analysis was used to combine the effect values of IVW methods in different data sources.ResultsWeight, BMI, body fat percentage, waist circumference, hip circumference and BMR analyses showed causal association with increased KOA risk, while WHR analysis indicated a reduction of the incidence of KOA. P-value for all the results was less than 0.05 and F-value large than 20. All results were negative for heterogeneity tests and sensitivity analyses, and there was pleiotropy in weight and BMR. Meta-analysis results showed that the results of Odds Ratios (95% Confidence Intervals) for Weight (1.43(1.35–1.51)), BMI (1.40(1.10–1.78)), body fat percentage (1.56(1.44–1.68)), waist circumference (1.40(1.10–1.78)), hip circumference (1.37(1.30–1.44)), WHR (0.86(0.71–1.04)) and BMR (1.36(1.27–1.46) were consistent with the ones by Mendelian randomization analyses.ConclusionsBody fat percentage may be a better indicator of KOA than BMI. In addition, weight and BMR may have a causal effect in KOA, but WHR does not have a causal relationship. BMI, body fat percentage, waist circumference, and hip circumference has a causal effect on KOA.

Anemia and testosterone deficiency risk: insights from NHANES data analysis and a Mendelian randomization analysis

Background Previous research has shown that testosterone deficiency (TD) increases the risk of anemia, but it is unclear whether anemia affects testosterone levels. This study investigated the influence of anemia on testosterone levels. Methods Utilizing data from six NHANES cycles, including demographic, testosterone levels, and hemoglobin concentrations, we employed multivariable-adjusted logistic regression to investigate the relationship between anemia and testosterone levels. Moreover, a two-sample Mendelian randomization (MR) study employing genome-wide association study (GWAS) data examined the causal relationship. Kaplan–Meier survival estimation was used to compared the overall survival (OS) of anemic and nonanemic patients with low testosterone and normal testosterone levels. Results The inclusion of 21,786 participants (2318 with anemia and19,468 without anemia) revealed that nonanemic patients exhibited higher testosterone levels than did anemic patients (β = 22.616, 95% CI: 3.873–41.359, p = 0.01807). MR analysis confirmed anemia as a cause of TD (OR = 1.045, 95% CI: 1.020–1.071, p < 0.001). Anemic males with low testosterone had reduced OS compared to those with normal levels (p < 0.001). Conclusions Anemia emerged as a potential risk factor for TD, highlighting a bidirectional relationship between these conditions. Additional prospective investigations are essential for the validation and reinforcement of our findings.

Mental illness and pulmonary tuberculosis: a bidirectional two-sample Mendelian randomization study

BackgroundObservational studies have confirmed that mental illness and pulmonary tuberculosis are closely related and increase each other’s incidence; however, whether there is a causal genetic association between the two diseases remains unknown. We attempted to answer this question using bidirectional two-sample Mendelian randomization (MR) in a large cohort study.MethodWe performed a bidirectional MR analysis between mental illness (major depressive, anxiety disorder, bipolar disorder, and schizophrenia) and pulmonary tuberculosis using summary statistics from genome-wide association studies in European individuals. The inverse-variance weighted method was used as the primary analytical method to assess causality. In addition, other additional MR methods (weighted median, MR–Egger, and weighted mode) were used to supplement the inverse-variance weighted results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability.ResultWe identified no causal genetic association between mental illness and pulmonary tuberculosis after applying the inverse variance weighted method (major depressive: odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.59–1.71, P = 0.98; anxiety disorder: OR = 1.72, 95% CI = 0.05–67.67, P = 0.76; bipolar disorder OR = 0.89, 95% CI = 0.66–1.22, P = 0.48; and schizophrenia: OR = 1.05, 95% CI = 0.91–1.20, P = 0.51). Similarly, pulmonary tuberculosis was not caustically associated with mental illness (major depressive: OR = 1.01, 95% CI = 1.00–1.02, P = 0.17; anxiety disorder: OR = 1.00, 95% CI = 0.99–1.01, P = 0.06; bipolar disorder: OR = 1.02, 95% CI = 0.98–1.07, P = 0.38; and schizophrenia: OR = 1.01, 95% CI = 0.97–1.05, P = 0.66).ConclusionOur research does not support a bidirectional causal association between the aforementioned mental illnesses and pulmonary tuberculosis.

The effects of fatty acids on psoriasis: A two-sample mendelian randomization study.

Some studies indicated an association between fatty acids (FA) and psoriasis. While definitive correlation between FA and psoriasis is still unclear. Therefore, our objective is to ascertain whether fatty acid levels are causally related to psoriasis using a Mendelian randomization approach. We investigated the causal relationship between psoriasis and multiple types of FA by mendelian randomization. All data were acquired from Genome-Wide Association Study. We also performed additional analysis to assess the validity of the causal connection. Our mendelian analysis suggests that n-3 fatty acid levels are associated with a lower risk of psoriasis. [IVW, OR/95% CI: 0.998/(0.997, 0.999), p (2.479 × 10-4)] Complementary analyses returned similar results, indicating consistency in our findings. No horizontal pleiotropy was found in our analysis. There was no indication of causal effects from other varieties of FA on psoriasis. Our studies found that n-3 FA may lower the likelihood of developing psoriasis. We also need well-designed prospective studies and related large-scale, multicenter RCTs to confirm our findings.

Metabolic Traits and Risk of Ischemic Stroke in Japanese and European Populations: A Two-Sample Mendelian Randomization Study

The role of metabolic traits in ischemic stroke (IS) has been explored through observational studies and a few Mendelian randomization (MR) studies employing limited methods in European populations. This study aimed to investigate the causal effects of metabolic traits on IS in both East Asian and European populations utilizing multiple MR methods based on genetic insights. Two-sample and multivariable MR were performed, and MR estimates were calculated as inverse-variance weighted (IVW), weighted median, and penalized weighted median. Pleiotropy was assessed by MR–Egger and Mendelian randomization pleiotropy residual sum and outlier tests. Systolic blood pressure (SBP) was associated with an increased risk of IS by IVW in both European (ORIVW: 1.032, 95% CI: 1.026–1.038, p &lt; 0.001) and Japanese populations (ORIVW: 1.870, 95% CI: 1.122–3.116, p = 0.016), which was further confirmed by other methods. Unlike the European population, the evidence for the association of diastolic blood pressure (DBP) with IS in the Japanese population was not stable. No evidence supported an association between the other traits and IS (all Ps &gt; 0.05) in both races. A positive association was found between SBP and IS in two races, while the results of DBP were only robust in Europeans.

Causal relationship between thyroid dysfunction and gastric cancer: a two-sample Mendelian randomization study

BackgroudGastric cancer is one of the most common cancers worldwide, and its development is associated with a variety of factors. Previous observational studies have reported that thyroid dysfunction is associated with the development of gastric cancer. However, the exact relationship between the two is currently unclear. We used a two-sample Mendelian randomization (MR) study to reveal the causal relationship between thyroid dysfunction and gastric cancer for future clinical work.Materials and methodsThis study is based on a two-sample Mendelian randomization design, and all data are from public GWAS databases. We selected hyperthyroidism, hypothyroidism, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) as exposures, with gastric cancer as the outcome. We used three statistical methods, namely Inverse-variance weighted (IVW), MR-Egger, and weighted median, to assess the causal relationship between thyroid dysfunction and gastric cancer. The Cochran’s Q test was used to assess the heterogeneity among SNPs in the IVW analysis results, and MR-PRESSO was employed to identify and remove IVs with heterogeneity from the analysis results. MR-Egger is a weighted linear regression model, and the magnitude of its intercept can be used to assess the horizontal pleiotropy among IVs. Finally, the data were visualized through the leave-one-out sensitivity test to evaluate the influence of individual SNPs on the overall causal effect. Funnel plots were used to assess the symmetry of the selected SNPs, forest plots were used to evaluate the confidence and heterogeneity of the incidental estimates, and scatter plots were used to assess the exposure-outcome relationship. All results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). P&amp;lt;0.05 represents statistical significance.ResultsAccording to IVW analysis, there was a causal relationship between hypothyroidism and gastric cancer, and hypothyroidism could reduce the risk of gastric cancer (OR=0.936 (95% CI:0.893-0.980), P=0.006).This means that having hypothyroidism is a protective factor against stomach cancer. This finding suggests that hypothyroidism may be associated with a reduced risk of gastric cancer.Meanwhile, there was no causal relationship between hyperthyroidism, FT4, and TSH and gastric cancer.ConclusionsIn this study, we found a causal relationship between hypothyroidism and gastric cancer with the help of a two-sample Mendelian randomisation study, and hypothyroidism may be associated with a reduced risk of gastric cancer, however, the exact mechanism is still unclear. This finding provides a new idea for the study of the etiology and pathogenesis of gastric cancer, and our results need to be further confirmed by more basic experiments in the future.

No bidirectional relationship between sleep phenotypes and risk of proliferative diabetic retinopathy: a two-sample Mendelian randomization study

This study aimed to investigate the probable existence of a causal relationship between sleep phenotypes and proliferative diabetic retinopathy (PDR). Single nucleotide polymorphisms associated with sleep phenotypes were selected as instrumental variables at the genome-wide significance threshold (P < 5 × 10−8). Inverse‐variance weighted was applied as the primary Mendelian randomization (MR) analysis method, and MR Egger regression, weighted median, simple mode, and weighted mode methods were used as complementary analysis methods to estimate the causal association between sleep phenotypes and PDR. Results indicated that genetically predicted sleep phenotypes had no causal effects on PDR risk after Bonferroni correction (P = 0.05/10) [Chronotype: P = 0.143; Daytime napping: P = 0.691; Daytime sleepiness: P = 0.473; Insomnia: P = 0.181; Long sleep duration: P = 0.671; Morning person:P = 0.113; Short sleep duration: P = 0.517; Obstructive sleep apnea: P = 0.091; Sleep duration: P = 0.216; and snoring: P = 0.014]. Meanwhile, there are no reverse causality for genetically predicted PDR on sleep phenotypes [Chronotype: P = 0.100; Daytime napping: P = 0.146; Daytime sleepiness: P = 0.469; Insomnia: P = 0.571; Long sleep duration: P = 0.779; Morning person: P = 0.040; Short sleep duration: P = 0.875; Obstructive sleep apnea: P = 0.628; Sleep duration: P = 0.896; and snoring: P = 0.047]. This study’s findings did not support the causal effect of between sleep phenotypes and PDR. Whereas, longitudinal studies can further verify results validation.