Mendelian randomization-Egger Research Articles

Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study.

Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.

Juvenile idiopathic arthritis and primary ovarian failure: a two-sample Mendelian randomization analysis in a mixed-gender cohort

BackgroundThe causal relationship between juvenile idiopathic arthritis (JIA) and primary ovarian failure (POF) remains uncertain. To elucidate this relationship, we employed a two-sample Mendelian randomization analysis.MethodsThe single nucleotide polymorphisms (SNPs) associated with JIA were obtained from a previously published genome-wide association study (GWAS), while the pooled data for POF originated from the FinnGen consortium. The study populations consisted exclusively of individuals of European descent. In our Mendelian randomization analysis, we performed inverse-variance weighted analysis, weighted-median analysis, weighted-mode analysis and Mendelian randomization-Egger regression analysis, supplemented by sensitivity analyses to validate the accuracy and robustness of the findings.ResultsThe IVW (OR = 1.23, 95% CI 1.06-1.43; P = 0.007) and weighted median (OR = 1.25, 95% CI 1.06-1.47; P = 0.009), along with sensitivity analysis validation, provide compelling evidence of a significant causal association between JIA and POF.ConclusionThe study revealed a significant causal association between genetically predicted JIA and POF, indicating that JIA significantly elevates the risk of developing POF. Therefore, it is recommended to implement screening for premature ovarian failure in women diagnosed with JIA.

Association of dietary nutrient intake with type 2 diabetes: A Mendelian randomization study.

Observational research suggests that the evidence linking dietary nutrient intake (encompassing minerals, vitamins, amino acids, and unsaturated fatty acids) to type 2 diabetes (T2D) is both inconsistent and limited. This study aims to explore the potential causal relationship between dietary nutrients and T2D. Causal estimation utilized Mendelian randomization techniques. Single nucleotide polymorphisms linked to dietary nutrients were identified from existing genome-wide association studies and used as instrumental variables. Genome-wide association studies data pertinent to T2D were sourced from the DIMANTE consortium and the FinnGen database. Techniques including inverse variance weighting (IVW), weighted mode, weighted median, and Mendelian randomization-Egger were employed for causal inference, complemented by sensitivity analysis. Genetically predicted higher phenylalanine (IVW: odds ratio = 1.10 95% confidence interval 1.04-1.17, P = 1.5 × 10-3, q_pval = 3.4 × 10-2) and dihomo-gamma-linolenic acid (IVW: odds ratio = 1.001 95% confidence interval 1.0006-1.003, P = 3.7 × 10-3, q_pval = 4.1 × 10-2) levels were directly associated with T2D risk. Conversely, no causal relationships between other nutrients and T2D were established. We hypothesize that phenylalanine and dihomo-gamma-linolenic acid contribute to the pathogenesis of T2D. Clinically, the use of foods with high phenylalanine content may pose potential risks for patients with a heightened risk of T2D. Our study provides evidence supporting a causal link between dietary nutrient intake and the development of T2D.

Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis.

Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal, reverse causal or correlative relationship remains unclear. We investigated this using a bidirectional 2-sample Mendelian randomization approach. We collected summary statistics for the primary analysis of chronic kidney disease (CKD) and AS from genome-wide association study meta-analyses including 480 698 and 653 867 participants, respectively. We collected further genome-wide association study summary statistics from up to 1 004 040 participants for sensitivity analyses involving estimated glomerular filtration rate (eGFR) derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. Inverse-variance weighted was the primary analysis method, with weighted-median, weighted-mode, Mendelian randomization-Egger, and Mendelian randomization-Pleiotropy Residual Sum and Outlier as sensitivity analyses. We did not find evidence of a causal relationship between genetically predicted CKD liability as the exposure and AS as the outcome (odds ratio [OR], 0.94 per unit increase in log odds of genetic liability to CKD [95% CI, 0.85-1.04], P=0.26) nor robust evidence of AS liability as the exposure and CKD as the outcome (OR, 1.04 per unit increase in log odds of genetic liability to AS [95% CI, 0.97-1.12], P=0.30). The sensitivity analyses were neutral overall, as were the analyses using eGFR derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. All positive controls demonstrated strong significant associations. The present study did not find evidence of a substantial effect of genetically predicted renal impairment on risk of AS. This has important implications for research efforts that attempt to identify prevention and treatment targets for both CKD and AS.

The gut microbiota-constipation connection: Insights from a two sample bidirectional Mendelian randomization study

ObjectiveThe dysbiosis of the gut microbiota has been implicated in various maladies. Research has identified an association between the dysbiosis of the gut microbiota and the risk of constipation, prompting this study to elucidate the potential causal relationship between gut microbiota imbalance with constipation through a two sample bidirectional Mendelian randomization (MR) study, shedding light on the genetic mechanisms underlying the connection between gut microbiota and constipation. MethodsThe forward MR analysis aimed to scrutinize whether alterations in the composition and abundance of gut microbiota impact the risk of constipation, while the reverse MR analysis explored whether the genetic predisposition to constipation influences the abundance of gut microbiota. Genomic correlation data for the gut microbiota were sourced from the comprehensive statistics of the MiBioGen consortium. Genomic correlation data for constipation were obtained from the IEU database, encoded as the dataset ebi-a-GCST90018829. The correlation was assessed using various analytical techniques, including inverse variance weighting (IVW), Mendelian randomization-Egger regression (MR-Egger), and weighted median and mode methodologies. To ensure the robustness of the results, a meticulous sensitivity analysis was conducted, incorporating Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and a Leave-one-out analysis. ResultsIn the forward Mendelian randomization analyses, a negative correlation was discerned between the abundance of Coprococcus in the gut microbiota and the occurrence of constipation (IVW: OR = 0.74, 95 % CI = 0.64–0.86, p = 0.0001), whereas a positive correlation was observed between the abundance of Bacteroidetes in the gut microbiota and constipation (IVW: OR = 1.22, 95 % CI = 1.00–1.50, p = 0.04). In the forward Mendelian randomization analyses, we were unsuccessful in obtaining valid instrumental variables for scrutiny, and we deemed that constipation exerts no influence on the composition of the gut microbiota. ConclusionGenetic predisposition towards increased abundance of Coprococcus and decreased abundance of Bacteroidetes is correlated with a diminished susceptibility to constipation. This investigation showed that alterations in the gut microbiota precipitated the onset of constipation, rather than constipation inducing modifications in the microbial flora.

Causal association between rheumatoid arthritis and an increased risk of age-related macular degeneration: A Mendelian randomization study.

This study's goal is to evaluate if there is a causal connection between rheumatoid arthritis (RA) and age-related macular degeneration (AMD), despite past epidemiological studies suggesting an association between the 2 disorders. The impact of RA on AMD is still unknown. Mendelian randomization (MR) was utilized in this study to assess the two-sample causal relationship between RA and AMD. Summary data from GWAS for RA and AMD in individuals with all European ancestries were gathered using the IEU GWAS database. The GWAS summary statistics of RA (14,361 RA patients and 43,923 healthy controls) and AMD (14,034 AMD patients and 91,214 controls participated) were obtained from the IEU GWAS database. After identifying suitable instrumental variables in line with the 3 MR assumptions, we conducted MR using the Mendelian randomization-Egger (MR-Egger), weighted median, and inverse variance weighting techniques. The MR-Egger intercept and MR-Polyvalent Residuals and Outliers methods were used to investigate the effects of horizontal pleiotropy. The leave-one-out strategy was used to prevent bias caused by certain single nucleotide polymorphisms. Sensitivity analysis was used to detect the heterogeneity. Using 50 single nucleotide polymorphisms as instrumental variables, this study examined the relationship between RA and AMD and discovered that RA increased the risk of AMD (inverse variance weighting odds ratio [OR] = 1.056, 95% confidence interval [CI] = 1.02-1.09, P = 5.44E-04; weighted median OR = 1.085, 95% CI = 1.04-1.14, P = 4.05E-04; MR-Egger OR = 1.074, 95% CI = 1.01-1.14, P = 2.18E-2). The current investigation demonstrated a causal link between AMD and RA. RA increased the risk of AMD. It is advised that future research concentrate on the processes underlying the relationship between RA and AMD.

Association between visceral adipose tissue and asthma based on the NHANES and Mendelian randomization study.

Obesity is a crucial risk factor for asthma. Observational studies have examined the association between abdominal obesity and asthma symptoms. This study aimed to investigate the causal relationship between visceral adipose tissue (VAT) and asthma and its potential as an independent indicator. This study utilized data from the National Health and Nutrition Examination Survey spanning 2011-8. Multivariable logistic regression and stratified variable selection were employed to identify associations between asthma and VAT. Moreover, a two-sample Mendelian randomization analysis, using 221 genetic variants as instrumental variables, was conducted to assess this relationship further. Our findings indicated that individuals with higher VAT levels were more likely to develop asthma. Visceral obesity remained a significant risk factor for asthma after adjusting for demographic characteristics. Genetic predictions suggest a positive association between VAT and an elevated risk of asthma (odds ratio [OR] = 1.393, 95% confidence interval [CI]: 1.266-1.534, and P = 1.43E-11). No significant polymorphisms were detected using the Mendelian randomization-Egger intercept test. This study presents potential evidence supporting the causal role of VAT in asthma development. Furthermore, the findings from the Mendelian randomization analysis further reinforce the relationship between VAT and asthma risk.

Study on the causal relationship between educational attainment and delirium: A two-sample Mendelian randomization study

This study aimed to investigate whether there is a causal relationship between educational attainment and delirium at the genetic level using the Mendelian randomization method, and provide new evidence for studies in this field. We found a causal relationship between educational attainment and delirium at the genetic level after excluding confounders using Mendelian randomization. The inverse variance weighting method of random effects was the main analysis method. The weighted median and Mendelian Randomization-Egger methods, as well as simple, and weighted modes were used as supplementary analysis methods. Additionally, horizontal pleiotropy tests were conducted, including the Mendelian Randomization-Egger intercept test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. Cochran's Q statistic was used to assess the size of heterogeneity. We retrieved all second single nucleotide polymorphism features and performed multivariate Mendelian randomization to adjust for the effect of potential confounders on our results. The inverse variance weighting suggested a negative correlation between genetically predicted educational attainment and delirium (0.67[0.49–0.92], p = 0.013); Mendelian Randomization Pleiotropy RESidual Sum and Outlier (0.67[0.49–0.92], p = 0.013) and multivariate Mendelian randomization (0.52[0.33–0.82], p = 0.005) results were generally consistent with the inverse variance weighting method. The Mendelian Randomization-Egger, simple, and weighted mode results were consistent with the inverse variance weighting results. Our results were not affected by pleiotropy or heterogeneity (p > 0.05, for both pleiotropy and heterogeneity). In addition, the “leave-one-out” analysis showed that the results of our Mendelian randomization analysis were not influenced by individual single nucleotide polymorphisms. Studies have found a causal relationship between educational attainment and delirium at the genetic level; higher educational attainment may be a protective factor against delirium. Clinically, more attention should be paid to patients at a high risk of delirium with low educational attainment.

Abstract 4443: Trans-population two-sample Mendelian randomization study of circulating metabolites and prostate cancer risk

Abstract While prostate cancer (PCa) is highly heritable, mechanisms underlying disease risk and PCa disparities are not well understood. Here, we conducted a two-sample Mendelian randomization (MR) to assess whether serum metabolites are causally associated with PCa risk in European, African, and Hispanic populations. MR analyses were performed on metabolite quantitative trait loci (mQTLs) for 250 metabolites quantified by untargeted mass spectroscopy via the Metabolon platform for 1,498 European and 1,740 African ancestry individuals from the Atherosclerosis Risk in Communities (ARIC) cohort and for 711 metabolites measured in 3,166 Hispanic individuals from the Hispanic Community Health Study/Study of Latinos (SOL). PCa GWAS summary statistics were obtained for men from European (122,188 cases, 604,640 controls), African (19,391 cases, 61,608 controls) and Hispanic (3,931 cases, 26,405 controls) populations from the PRACTICAL Consortium. Within each population, QTLs associated with metabolites at the genome-wide significance level (P&amp;lt;5x10-8) were included in instruments upon removing rare (minor allele frequency≤0.01) or correlated (R2≥0.2) SNPs calculated in ancestry-matched TOPMed populations. Inverse variance weighted (IVW) random effect models are presented as primary results. Sensitivity analyses were utilized to assess assumption violations (weighted mode, weighted median and MR egger). MR were conducted separately in each population, and fixed effect meta-analyses were conducted across population-specific MR results to identify trans-population associations. A false discovery rate was implemented to account for multiple testing. In total, 22, 4 and 1 metabolites significantly associated with PCa risk in Hispanic, European and African populations, respectively. Of these, 13 metabolites had a MR instrument in ≥1 population, 12 of which were significant following a trans-population meta-analysis, including 5 fatty acids, 3 lysophospholipids, 1 amino acid, 1 carbohydrate, 1 nucleotide and 1 xenobiotic. All fatty acids were associated with decreased PCa odds (2%-10%), as were 4 other metabolites (amino acid 3-methyoxytyrosine, nucleotide 5-methyluridine and lysophospholipids 1-archidonoyl-GPC (20:4n6) and 1-archidonoyl-GPE (20:4n6), 4%-9%). The 3 remaining metabolites, erythritol, 1-linoleoyl-GPE (18:2) and mannose, were found to increase PCa odds by 10%, 6% and 4%, respectively. Additional metabolite harmonization efforts are underway to conduct trans-population analyses metabolome-wide. This study provides evidence of associations between metabolites, such as fatty acids and lysophysopholipids, and PCa across diverse populations. These findings point to mechanisms that could inform preventive or therapeutic strategies pending functional investigations. Multivariable and bidirectional MR are ongoing to further assess findings. Citation Format: Harriett Fuller, Rebecca Rohde, Heather Highland, Jiayi Shen, Bing Yu, Eric Boerwinkle, Megan Grove, Kari E. North, David V. Conti, Christopher A. Haiman, Kristin Young, Burcu Darst. Trans-population two-sample Mendelian randomization study of circulating metabolites and prostate cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4443.

Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study.

Clinical studies have reported that patients with gastroesophageal reflux disease (GERD) have a higher prevalence of hypertension. To performed a bidirectional Mendelian randomization (MR) analysis to investigate the causal link between GERD and essential hypertension. Eligible single nucleotide polymorphisms (SNPs) were selected, and weighted median, inverse variance weighted (IVW) as well as MR egger (MR-Egger) regression were used to examine the potential causal association between GERD and hypertension. The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs. The MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of single instrumental variable. IVW analysis exhibited an increased risk of hypertension (OR = 1.46, 95%CI: 1.33-1.59, P = 2.14E-16) in GERD patients. And the same result was obtained in replication practice (OR = 1.002, 95%CI: 1.0008-1.003, P = 0.000498). Meanwhile, the IVW analysis showed an increased risk of systolic blood pressure (β = 0.78, 95%CI: 0.11-1.44, P = 0.021) and hypertensive heart disease (OR = 1.68, 95%CI: 1.36-2.08, P = 0.0000016) in GERD patients. Moreover, we found an decreased risk of Barrett's esophagus (OR = 0.91, 95%CI: 0.83-0.99, P = 0.043) in essential hypertension patients. We found that GERD would increase the risk of essential hypertension, which provided a novel prevent and therapeutic perspectives of essential hypertension.

Evidence for Genetic Causal Relationships Between Multiple Immune-Mediated Inflammatory Diseases and Age-Related Macular Degeneration: A Univariable and Multivariable Mendelian Randomization Study.

With the global aging population on the rise, age-related macular degeneration (AMD) poses a growing healthcare burden. Prior research hints at immune-mediated inflammatory diseases (IMIDs) potentially elevating AMD risk via diverse mechanisms. However, causality remains disputed as a result of confounding factors. Hence, our Mendelian randomization (MR) study aims to untangle this link, mitigating confounding effects to explore the IMID-AMD causal relationship. This study aims to investigate the causal relationship between IMIDs and AMD, providing new strategies for the prevention and treatment of AMD in clinical practice. This study was registered with PROSPERO, CRD42023469815. We obtained data on IMIDs and AMD from Genome-Wide Association Studies (GWAS) summary statistics and the FinnGen consortium. Rigorous selection steps were applied to screen for eligible instrumental single nucleotide polymorphisms (SNPs). We conducted univariate Mendelian randomization, inverse variance-weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger), and multivariate Mendelian randomization (MVMR) analyses. Various sensitivity analysis methods were employed to assess pleiotropy and heterogeneity. The aim was to explore the causal relationships between IMIDs and AMD. The MR analysis revealed that Crohn's disease (CD) (IVW: odd ratios (OR) 1.05, 95%CI (confidence interval) 1.01-1.10, p = 0.007), rheumatoid arthritis (RA) (IVW: OR 1.09, 95%CI 1.04-1.15, p = 0.0001), and type1 diabetes (T1D) (IVW: OR 1.05, 95%CI 1.02-1.09, p = 0.001) were correlated with an elevated risk of AMD, while multiple sclerosis (MS) (IVW: OR 2.78E-18, 95%CI 2.23E-31 to 3.48E-05, p = 0.008) appeared to be protective against AMD. These findings were supported by an array of MR analysis methodologies and the MVMR approach. Our study results, based on MR, provide genetic evidence indicating a causal relationship between specific IMIDs and AMD. CD, RA, and T1D are factors increasing the risk of AMD, while MS may have a protective effect.

Bidirectional causal relationship between psychiatric disorders and osteoarthritis: A univariate and multivariate Mendelian randomization study.

Observational studies have shown associations between psychiatric disorders and osteoarthritis (OA). However, the causal impact of different psychiatric disorder types on specific sites of osteoarthritis remains unclear. This study aimed to comprehensively understand the potential causal associations between psychiatric disorders and osteoarthritis using Mendelian randomization (MR) analysis. We collected data from genome-wide association studies of knee osteoarthritis (KOA) (n=403,124), hip osteoarthritis (HOA) (n=393,873), osteoarthritis of the knee or hip (KHOA) (n=417,596), as well as three psychiatric disorders: bipolar disorder (n=41,917), major depressive disorder (n=170,756), and schizophrenia (n=76,755) among European populations. We applied bidirectional univariate and multivariate MR analyses, including inverse variance weighted, Mendelian randomization-Egger, weighted median, simple mode, and weighted mode. We considered p<.05 as a criterion for identifying potential evidence of association. Bonferroni correction was used for multiple tests. Our univariate MR analysis results demonstrated that bipolar disorder is a protective factor for KOA (OR=0.90, 95% CI=0.83 to 0.97, p=0.0048) and may also be protective for KHOA (p=0.02). Conversely, major depression has a positive causal effect on both KOA (OR=1.27; 95% CI=1.08 to 1.49; p=0.0036) and KHOA (OR=1.24; 95% CI=1.12 to 1.37; p=3.62×10-05 ). Furthermore, our analysis suggested that KHOA may be a risk factor for major depression (OR=1.06; 95% CI=1.00 to 1.12; p=0.0469) in reverse MR. After adjusting smoking (OR=1.46; 95% CI=1.19 to 1.65; p=0.0032) and body mass index (OR=1.44; 95% CI=1.09 to 1.81; p=8.56×10-04 ), the casual association between major depression and KHOA remained. Our study indicates that major depression is a great risk factor for KHOA, increasing the likelihood of their occurrence. However, further in-depth studies will be required to validate these results and elucidate the underlying molecular mechanisms.

The causal relationship between 41 inflammatory cytokines and hypothyroidism: bidirectional two-sample Mendelian randomization study.

Investigating the association between inflammatory cytokines and hypothyroidism remains challenging due to limitations in traditional observational studies. In this study, we employed Mendelian randomization (MR) to assess the causal relationship between 41 inflammatory cytokines and hypothyroidism. Inflammatory cytokines in 30,155 individuals of European ancestry with hypothyroidism and in a GWAS summary containing 8,293 healthy participants were included in the study for bidirectional two-sample MR analysis. We utilized inverse variance weighting (IVW), weighted median (WM), and Mendelian randomization-Egger (MR-Egger) methods. Multiple sensitivity analyses, including MR-Egger intercept test, leave-one-out analysis, funnel plot, scatterplot, and MR-PRESSO, were applied to evaluate assumptions. We found evidence of a causal effect of IL-7 and macrophage inflammatory protein-1β (MIP-1β) on the risk of hypothyroidism, and a causal effect of hypothyroidism on several cytokines, including granulocyte colony-stimulating factor (G-CSF), IL-13, IL-16, IL-2rα, IL-6, IL-7, IL-9, interferon-γ-inducible protein 10 (IP10), monokine induced by interferon (IFN)-γ (MIG), macrophage inflammatory protein-1β (MIP-1β), stem cell growth factors-β (SCGF-β), stromal cell derived factor-1α (SDF-1α), and tumor necrosis factor-α (TNF-α). Our study suggests that IL-7 and MIP-1β may play a role in the pathogenesis of hypothyroidism, and that hypothyroidism may induce a systemic inflammatory response involving multiple cytokines. These findings may have implications for the prevention and treatment of hypothyroidism and its complications. However, further experimental studies are needed to validate the causal relationships and the potential of these cytokines as drug targets.

Associations between lipid-lowering drugs and pregnancy and perinatal outcomes: a Mendelian randomization study.

Mounting evidence has indicated that maternal dyslipidemia is associated with adverse obstetric outcomes, and the actions of lipid-lowering drugs in pregnant women remain controversial. Hence, this study aimed to appraise the causal relationship of lipid-lowering drugs [hydroxymethylglutaryl-coenzyme reductase (HMGCR) inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors] with pregnancy and perinatal outcomes using drug-targeting Mendelian randomization analysis. As a proxy for lipid-lowering drug exposure, two genetic instruments were used: genetic variants within or near the gene linked to low-density lipoprotein cholesterol (LDL-C) and the expression of quantitative trait loci of the drug target gene. Effect estimates were calculated using the inverse variance weighting (IVW) method and summary data-based Mendelian randomization (SMR) method. Heterogeneity and pleiotropy were assessed by Mendelian randomization-Egger regression, the Cochran Q test, and MR-PRESSO analysis. HMGCR inhibitors were ascribed to a reduced risk of preeclampsia in both the IVW-MR method [odds ratio (OR) 0.583; 95% confidence interval (CI) 0.418-0.812; P = 0.001] and SMR analysis (OR 0.816; 95% CI 0.675-0.986; P = 0.036). The causal link between HMGCR inhibitors and offspring birthweight was statistically significant only in the analysis using the IVW method (OR, 0.879; 95% CI, 0.788-0.980; P = 0.020), and the combined results of the OR values supported the potential inhibitory effect of HMGCR inhibitors on offspring birthweight. Causal associations between lipid-lowering drugs and gestational diabetes, preterm birth, and congenital anomalies were not detected in either analysis. No causal associations were observed between lipid-lowering drugs and gestational diabetes, preterm birth or congenital anomalies, whereas genetically predicted HMGCR inhibition dramatically reduced the risk of preeclampsia but attenuated offspring birthweight.

Investigation of causal relationships between cortical structure and osteoporosis using two-sample Mendelian randomization.

The mutual interaction between bone characteristics and brain had been reported previously, yet whether the cortical structure has any relevance to osteoporosis is questionable. Therefore, we applied a two-sample bidirectional Mendelian randomization analysis to investigate this relationship. We utilized the bone mineral density measurements of femoral neck (n = 32,735) and lumbar spine (n = 28,498) and data on osteoporosis (7300 cases and 358,014 controls). The global surficial area and thickness and 34 specific functional regions of 51,665 patients were screened by magnetic resonance imaging. For the primary estimate, we utilized the inverse-variance weighted method. The Mendelian randomization-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis were conducted to assess heterogeneity and pleiotropy. We observed suggestive associations between decreased thickness in the precentral region (OR = 0.034, P = 0.003) and increased chance of having osteoporosis. The results also revealed suggestive causality of decreased bone mineral density in femoral neck to declined total cortical surface area (β = 1400.230mm2, P = 0.003), as well as the vulnerability to osteoporosis and reduced thickness in the Parstriangularis region (β = -0.006mm, P = 0.002). Our study supports that the brain and skeleton exhibit bidirectional crosstalk, indicating the presence of a mutual brain-bone interaction.

No Causal Association Between Inguinal Hernia and Aortic Aneurysm Using Mendelian Randomization Analysis.

Aortic aneurysm (AA) is a serious disease that affects the aging population worldwide. Potential risk or associated factors, such as inguinal hernia, have been suggested by conventional studies. In the present study, summary statistics data for the associations of inguinal hernia were derived from a large genome-wide association study including 18,791 inguinal hernia cases and 93,955 controls in the UK Biobank. Corresponding data of AA were extracted from FinnGen, comprising 7603 cases and 317,899 controls in Finland. The causal association was assessed using Mendelian Randomization-Egger, weighted median, and inverse variance weighting methods, and compared with observational estimates previously published. Our analysis found no convincing causal effect between genetically predicted inguinal hernia and the risk of AA (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.85-1.31, P = .65), abdominal aortic aneurysm (AAA, OR = 1.15, 95% CI = 0.92-1.46, P = .22), and thoracic aortic aneurysm (TAA, OR = 1.05, 95% CI = 0.85-1.30, P = .67). The results are in contrast to previous observational evidence suggesting a potentially common causal association between inguinal hernia and AA. Further research is needed to better understand the interplay between risk factors and their impact on aneurysm development.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.

Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Evaluation of bidirectional relationships between risk preference and mood disorders: A 2-sample Mendelian randomization study

BackgroundRisk preference is often defined as the tendency to engage in risky activities. Increasing evidence shows that risk preference is associated with mood disorders. However, the causality and direction of this association are not clear. MethodsGenome-wide association study summary data of risk preference in 939,908 participants from UK Biobank and 23andMe were used to identify general risk preference. Data for 413,466 individuals taken from The Psychiatric Genomics Consortium were used to identify bipolar disorder (BP). Data for 807,553 individuals taken from The Psychiatric Genomics Consortium were used to identify major depressive disorder (MDD). The weighted median, inverse-variance weighting, and Mendelian randomization-Egger methods were used for the Mendelian randomization analysis to estimate a causal effect and detect directional pleiotropy. ResultsGWAS summary data were obtained from three combined samples, containing 939,908, 413,466 and 807,553 individuals of European ancestry. Mendelian randomization evidence suggested that risk preference increased the onset of BP, and BP also increased risk preference (P < 0.001). In contrast, there were no reliable results to describe the relationship of risk preference with MDD (P > 0.05). Furthermore, there was no significant relationship between MDD and risk preference. ConclusionUsing large-scale GWAS data, robust evidence supports a mutual relationship between risk preference and BP, but no relationship between risk preference and MDD was observed. This study indicates a potential marker for the early identification of MDD and BP. Additionally, it shows that reducing risk preferences for patients with BP may be a valuable intervention for treating BP.

Causal relationship between gut microbiota and myasthenia gravis: a bidirectional mendelian randomization study

BackgroundObservational studies have demonstrated an association between gut microbiota and myasthenia gravis; however, the causal relationship between the two still lacks clarity. Our goals are to ascertain the existence of a bidirectional causal relationship between gut microbiota composition and myasthenia gravis, and to investigate how gut microbiota plays a role in reducing the risk of myasthenia gravis.MethodsWe acquired gut microbiota data at the phylum, class, order, family, and genus levels from the MiBioGen consortium (N = 18,340) and myasthenia gravis data from the FinnGen Research Project (426 cases and 373,848 controls). In the two-sample Mendelian randomization analysis, we assessed the causal relationship between the gut microbiota and myasthenia gravis. We also conducted bidirectional MR analysis to determine the direction of causality. The inverse variance weighted, mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to test the causal relationship between the gut microbiota and severe myasthenia gravis. We used MR-Egger intercept and Cochran's Q test to assess for pleiotropy and heterogeneity, respectively. Furthermore, we utilized the MR-PRESSO method to evaluate horizontal pleiotropy and detect outliers.ResultsIn the forward analysis, the inverse-variance weighted method revealed that there is a positive correlation between the genus Lachnoclostridium (OR = 2.431,95%CI 1.047–5.647, p = 0.039) and the risk of myasthenia gravis. Additionally, the family Clostridiaceae1 (OR = 0.424,95%CI 0.202–0.889, p = 0.023), family Defluviitaleaceae (OR = 0.537,95%CI 0.290–0.995, p = 0.048), family Enterobacteriaceae (OR = 0.341,95%CI 0.135–0.865, p = 0.023), and an unknown genus (OR = 0.407,95%CI 0.209–0.793, p = 0.008) all demonstrated negative correlation with the risk of developing myasthenia gravis. Futhermore, reversed Mendelian randomization analysis proved a negative correlation between the risk of myasthenia gravis and genus Barnesiella (OR = 0.945,95%CI 0.906–0.985, p = 0.008).ConclusionOur research yielded evidence of a causality connection in both directions between gut microbiota and myasthenia gravis. We identified specific types of microbes associated with myasthenia gravis, which offers a fresh window into the pathogenesis of this disease and the possibility of developing treatment strategies. Nonetheless, more studies, both basic and clinical, are necessary to elucidate the precise role and therapeutic potential of the gut microbiota in the pathogenesis of myasthenia gravis.

The causal relationship between COVID-19 and seventeen common digestive diseases: a two-sample, multivariable Mendelian randomization study

ObjectivesIn clinical practice, digestive symptoms such as nausea, vomiting are frequently observed in COVID-19 patients. However, the causal relationship between COVID-19 and digestive diseases remains unclear.MethodsWe extracted single nucleotide polymorphisms associated with the severity of COVID-19 from summary data of genome-wide association studies. Summary statistics of common digestive diseases were primarily obtained from the UK Biobank study and the FinnGen study. Two-sample Mendelian randomization analyses were then conducted using the inverse variance-weighted (IVW), Mendelian randomization-Egger regression (MR Egger), weighted median estimation, weighted mode, and simple mode methods. IVW served as the primary analysis method, and Multivariable Mendelian randomization analysis was employed to explore the mediating effect of body mass index (BMI) and type 2 diabetes.ResultsMR analysis showed that a causal association between SARS-CoV-2 infection (OR = 1.09, 95% CI 1.01–1.18, P = 0.03), severe COVID-19 (OR = 1.02, 95% CI 1.00–1.04, P = 0.02), and COVID-19 hospitalization (OR = 1.04, 95% CI 1.01–1.06, P = 0.01) with gastroesophageal reflux disease (GERD). Mediation analysis indicated that body mass index (BMI) served as the primary mediating variable in the causal relationship between SARS-CoV-2 infection and GERD, with BMI mediating 36% (95% CI 20–53%) of the effect.ConclusionsWe found a causal relationship between SARS-CoV-2 infection and gastroesophageal reflux disease. Furthermore, we found that the causal relationship between SARS-CoV-2 infection and GERD is mainly mediated by BMI.