Multivariable Mendelian Randomization Research Articles

Combined single-cell RNA sequencing and mendelian randomization to identify biomarkers associated with necrotic apoptosis in intervertebral disc degeneration

BackgroundIntervertebral disc degeneration (IDD) is associated with back pain; back pain is a world-wide contributor to poor quality of life, while necroptosis has the characteristics of necroptosis and apoptosis, however, its role in IDD is still unclear. Therefore, the aim of this study was to identify biomarkers associated with necroptosis in IDD. PurposeTo explore biomarkers associated with necroptosis in IDD, reveal the pathogenesis of IDD, as well as provide new directions for the diagnosis and treatment of this disease. Study design/settingsRetrospective cohort study. Our study employs scRNA-seq coupled with MR analysis to investigate the causal relationship between necroptosis and IDD, laying a foundational groundwork for unveiling the intricate pathogenic mechanisms of this condition. MethodsData quality control and normalisation was executed in single-cell dataset, GSE205535. Then, different cell types were obtained by cell annotation through marker genes. Subsequently, chi-square test was employed to assess the distribution difference of different cell types between IDD and control to screen key cells. AUCell was applied to calculate necroptosis-related genes (NRGs) scores of all cell types, further key cells were divided into high and low NRGs groups according to the median AUC scores of different cell types. Afterwards, the differentially expressed genes (DEGs) within the two score groups were screened. Then, the genes that had causal relationship with IDD were selected as biomarkers by univariate and multivariate Mendelian randomization (MR) analysis. Finally, the expression of biomarkers in different cell types and pseudo-time analysis was analyzed separately. ResultsIn GSE205535, 16 different cell populations identified by UMAP cluster analysis were further annotated to 8 cell types using maker genes. Afterwards, 53 DEGs were screened between the high and low NRGs groups. In addition, 9 genes with causal relationship with IDD were obtained by univariate MR analysis, further multivariate MR analysis proved that NT5E and TMEM158 had a direct causal relationship with IDD, which were used as biomarkers in this study. This study not only found that the expression levels of NT5E and TMEM158 were higher in IDD group, but also found that fibrochondrocytes and inflammatory chondrocytes were the key cells of NT5E and TMEM158, respectively. In the end, the biomarkers had the same expression trend in the quasi-time series, and both of them from high to low and then increased. ConclusionNT5E and TMEM158, as biomarkers of necroptotic apoptotic IDD, were causally associated with IDD. clinical significanceThe understanding of chondrocytes as key cells provides new perspectives for deeper elucidation of the pathogenesis of IDD, improved diagnostic methods, and the development of more effective treatments. These findings are expected to provide a more accurate and personalised approach to clinical diagnosis and treatment, thereby improving the prognosis and quality of life of patients with IDD.

Integrative Metabolomics Differentiate Coronary Artery Disease, Peripheral Artery Disease, and Venous Thromboembolism Risks.

Arterial and venous cardiovascular conditions, such as coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE), are genetically correlated. Interrogating underlying mechanisms may shed light on disease mechanisms. In this study, we aimed to identify (1) epidemiological and (2) causal, genetic relationships between metabolites and CAD, PAD, and VTE. We used metabolomic data from 95 402 individuals in the UK Biobank, excluding individuals with prevalent cardiovascular disease. Cox proportional-hazards models estimated the associations of 249 metabolites with incident disease. Bidirectional 2-sample Mendelian randomization (MR) estimated the causal effects between metabolites and outcomes using genome-wide association summary statistics for metabolites (n=118 466 from the UK Biobank), CAD (n=184 305 from CARDIoGRAMplusC4D 2015), PAD (n=243 060 from the Million Veterans Project), and VTE (n=650 119 from the Million Veterans Project). Multivariable MR was performed in subsequent analyses. We found that 196, 115, and 74 metabolites were associated (P<0.001) with CAD, PAD, and VTE, respectively. Further interrogation of these metabolites with MR revealed 94, 34, and 9 metabolites with potentially causal effects on CAD, PAD, and VTE, respectively. There were 21 metabolites common to CAD and PAD and 4 common to PAD and VTE. Many putatively causal metabolites included lipoprotein traits with heterogeneity across different sizes and lipid subfractions. Small VLDL (very-low-density lipoprotein) particles increased the risk for CAD while large VLDL particles decreased the risk for VTE. We identified opposing directions of CAD and PAD effects for cholesterol and triglyceride concentrations within HDLs (high-density lipoproteins). Subsequent sensitivity analyses including multivariable MR revealed several metabolites with robust, potentially causal effects of VLDL particles on CAD. While common vascular conditions are associated with overlapping metabolomic profiles, MR prioritized the role of specific lipoprotein species for potential pharmacological targets to maximize benefits in both arterial and venous beds.

Genetic Associations of Lipids and Lipid-Modifying Drug Targets With Type 2 Diabetes in the Chinese Population

BackgroundDyslipidemia is a recognized risk factor for type 2 diabetes (T2D), yet the genetic basis and causal nature remain unclear, particularly in Chinese populations. ObjectivesThe authors investigated the causal effects of genetically predicted lipid levels on T2D risk and explored the potential effects of lipid-modifying drugs. MethodsLeveraging data from the Kunshan Community cohort in China, we analyzed the associations between low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides (TGs) with T2D risk using genetic risk scores, 1-sample univariable, multivariable, and nonlinear Mendelian randomization (MR) analyses. Two-sample MR using summary-level data from Global Lipid Genetics Consortium and Biobank Japan was used for validation. Drug-target MR was used to examine the impact of lipid-modifying drug targets on T2D. ResultsLower genetic risk scores of LDL-C (OR per SD: 0.97 [95% CI: 0.95-0.99]; P = 0.010) and TGs (0.96 [95%CI: 0.94-0.98]; P = 0.002) were associated with increased T2D risk. Univariable MR revealed that genetically predicted lower LDL-C (0.78 [95% CI: 0.65-0.93]; P = 0.006) and TG levels (0.76 [95% CI: 0.66-0.89]; P < 0.001) were linked to a higher T2D risk, validated by 2-sample MR. Multivariable MR demonstrated a direct inverse association between LDL-C (0.80 [95% CI: 0.66-0.97]; P = 0.020) and TG (0.80 [95% CI: 0.66-0.97]; P = 0.022) with T2D. No evidence was found for nonlinearity. Among lipid-modifying drugs, genetic mimicry of apolipoprotein C3 (APOC3) inhibition increased T2D risk (OR per 1 mmol/L reduction in TG: 1.38 [95% CI: 1.10-1.75]; P = 0.007). ConclusionsOur findings suggested potential adverse effects of lower LDL-C, TG levels, as well as long-term use of APOC3 inhibitors on T2D risk in Chinese populations. These findings highlight the need for cautious lipid management strategies in T2D prevention.

Abstract P192: The Impact of Sleep Apnea on Preeclampsia or Eclampsia: The Mediation Role of Large High-Density Lipoprotein Components

Introduction: Sleep apnea is increasingly recognized as a significant risk factor for preeclampsia/eclampsia (PE). Research increasingly shows that large high-density lipoprotein (L-HDL) may influence the PE development. This study aimed to investigate the association between sleep apnea and PE and the proportion of this association that is mediated through different L-HDL components. Hypothesis: Modifications in the L-HDL components induced by sleep apnea significantly contribute to the pathogenesis of PE. Methods: A two-sample Mendelian randomization (MR) was conducted using genetic variants associated with relative sleep apnea from the FinnGen study and different L-HDL components from UK Biobank. The single-nucleotide polymorphisms (SNPs) were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. Then the multivariable MR analysis was performed to estimate the effect of the mediators on the risk of PE with adjustment for sleep apnea. The MR-Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) were mainly used for sensitivity analyses. In mediation analyses, the direct effect of different L-HDL components estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Results: This study found that sleep apnea significantly affects the risk of PE, as well as various L-HDL components, including large high-density lipoprotein cholesterol (L-HDL-C), large high-density lipoprotein cholesteryl ester (L-HDL-CE), large high-density lipoprotein concentration (L-HDL concentration), cholesterol to total lipids ratio in large high-density lipoprotein (C/TL-L-HDL), cholesteryl esters to total lipids ratio in large high-density lipoprotein (CE/TL-L-HDL), and phospholipids to total lipids ratio in large high-density lipoprotein (P/TL-L-HDL). In multivariable MR analysis, these components were also significantly associated with the risk of PE. Additionally, mediation analysis identified P/TL-L-HDL as the only significant mediator between sleep apnea and PE (mediation effect = 0.0224; 95% CI=0.0005, 0.0443; p-value=0.0455). Conclusion: This study establishes a causal link between sleep apnea and an increased risk of preeclampsia/eclampsia, mediated by P/TL-L-HDL. Key Words: Sleep apnea; Preeclampsia; Eclampsia; Large HDL; Mendelian randomization; Mediation analysis

Bidirectional Causal Association Between Chronic Obstructive Pulmonary Disease and Cardiovascular Diseases: A Mendelian Randomization Study.

A large number of studies have demonstrated links between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVDs). However, the causal relationship between COPD and CVDs and the reverse causality remains divergent. Exposure and outcome data from the largest available genome-wide association studies were extracted for Mendelian randomization (MR) studies. Univariate MR analysis was performed using IVW as the primary analysis method, and multiple sensitivity analyses were used to enhance the robustness of the results. Furthermore, this was followed by mediation MR analysis of positive results after excluding confounding factors with multivariable MR analysis. The MR estimation based on IVW method indicated a strong association between genetically determined COPD and heart failure (HF) (OR = 1.117, 95% CI: 1.066-1.170, p <0.001), coronary heart disease (CHD) (OR = 1.004, 95% CI: 1.002-1.006, p <0.001), essential hypertension (EH) (OR = 1.009, 95% CI: 1.005-1.013, p <0.001) as well as Stroke (OR = 1.003, 95% CI: 1.001-1.004, p <0.001). The results of multivariable MR analysis revealed that COPD is not significantly associated with CHD after adjusting for IL-6, LDL, or total cholesterol (p>0.05). Our findings indicated that BMI, smoking initiation, smoking status, obesity, and FEV1 played a role in the causal effect of COPD on HF, EH, and Stroke. We found positive causal relationships between COPD and HF, EH, and Stroke essentially unaffected by other confounding factors. The causal relationship exhibited between COPD and CHD was influenced by confounding factors. BMI, obesity, initiation of smoking, smoking status, and FEV1 were the mediators between COPD and CVDs.

Causal effects of female reproductive features on nonalcoholic fatty liver disease: A mendelian randomization study.

Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study. Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity. There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736-0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791-0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511-0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT. This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.

Branched-chain amino acids and risk of lung cancer: insights from mendelian randomization and NHANES III.

Recent studies have observed the relationships of circulatory and dietary intake of branched-chain amino acids (BCAAs) with long-term risk of certain cancers. However, the exact causality of BCAA with lung cancer (LUCA) and its pathological subtypes remains obscure. The aim of this study is to investigate the association between BCAA metabolism and risk of LUCA. Here we conducted Mendelian randomization (MR) and observational epidemiological analyses to investigate the association between BCAA and risk of LUCA. With single nucleotide polymorphism (SNP)-phenotype association data extracted from genome-wide association studies (GWAS), we performed univariate and multivariate MR analyses to infer the causal effect of circulatory BCAA concentrations on LUCA. We further investigated the effects of several potential mediators and quantified the mediation effects. Population-level analyses were performed in the National Health and Nutrition Examination Survey (NHANES) III. Our results demonstrated that genetically predicted circulatory valine concentrations causally increased the risk of overall LUCA [odds ratio (OR) =1.324, 95% confidence interval (CI): 1.058-1.658, P=0.01]. For pathological subgroups, elevated levels of leucine, isoleucine, valine, and total BCAA were founded to be significantly associated with a higher risk of squamous cell lung cancer (LUSC); however, they did not significantly affect lung adenocarcinoma (LUAD). Moreover, body mass index (BMI) mediated approximately 3.91% (95% CI: 1.22-7.18%) of the total effect of leucine on LUSC. In the NHANES III population, dietary total BCAA intake was significantly associated with BMI ≥30 kg/m2, while no non-linear relationships were observed. This study provides genetic evidence for the histology-specific causality of BCAA on LUCA and implies the mediation role of BMI in this relationship. Further studies are needed to confirm these findings and elucidate the underlying mechanisms.

Association between common chronic pulmonary diseases and lung cancer: Mendelian randomization analysis

BackgroundLung cancer is a leading public health concern worldwide. Previous evidence suggests that chronic obstructive pulmonary disease (COPD) and asthma may contribute to its development. However, whether these common chronic pulmonary diseases are causal factors of lung cancer remained unclear.MethodsSummary statistics from genome-wide association studies (GWAS) were used for Mendelian randomization (MR) analysis. Genetic data for COPD were obtained from the Global Biobank Meta-Analysis Initiative, and asthma data were retrieved from the UK Biobank cohort. Suitable instrumental variables were selected based on quality control measures. GWAS summary data for lung cancer were obtained from a large study involved 85,716 participants. MR analysis was performed using various methods, and sensitivity analyses were conducted. Multivariable MR (MVMR) analysis was employed to account for potential confounding factors.ResultsOur MR analysis revealed a significant causal association between COPD and lung cancer, including its subtypes such as lung squamous cell carcinoma, lung adenocarcinoma, and small cell lung carcinoma. Genetically predicted COPD was associated with a 64% increased risk of lung cancer and a 2.3 to 2.8-fold increased risk of the different subtypes. However, in the MVMR analysis adjusting for smoking, alcohol drinking, and body mass index, the association between COPD and lung cancer became non-significant. No significant association was observed between asthma (childhood-onset and adult-onset) and lung cancer and its histological subtypes.ConclusionsOur study suggests a potential causal association between COPD and lung cancer. However, this association became non-significant after adjusting for smoking in the multivariable analysis.

IL-16 Mediates the Effect of Circulating Metabolites on Postmenopausal Osteoporosis: A Two-Step, Multivariable Mendelian Randomization Study.

Objectives: This study aimed to explore the relationship between circulating metabolites and postmenopausal osteoporosis (PMOP) and to assess the mediating role of inflammatory factors. Methods: Utilizing summary-level data from genome-wide association studies (GWAS) and employing a Mendelian Randomization approach, a two-sample MR analysis was conducted to assess the relationship between circulating metabolites and PMOP. Additionally, a two-step MR was used to quantify the mediating impact of inflammatory factors on the effect of circulating metabolites on PMOP. Results: The results revealed a significant association between certain metabolites and the risk of PMOP, notably the ratio of free cholesterol to total lipids in very large VLDL particles (OR: 1.399, 95% CI: 1.002-1.954, p = 0.048) and IL-16 (OR: 0.773, 95% CI: 0.608-0.983, p = 0.036). IL-16 was found to partially mediate the impact of circulating metabolites on PMOP, with a mediation effect of 10.4%. Conclusion: This study underscores the crucial role of circulating metabolites and inflammatory factors in PMOP pathogenesis. A causal relationship between circulating metabolites and PMOP was established, with IL-16 mediating some effects. These findings hold promise for clinical applications in early detection, personalized medicine, and the identification of therapeutic targets for PMOP.

Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia

BackgroundClinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear. MethodsThis work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes. ResultsCombining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70–3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06–3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88–3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %. ConclusionOur study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.

Causal relationships between GLP1 receptor agonists, blood lipids, and heart failure: a drug-target mendelian randomization and mediation analysis

BackgroundGlucagon-like peptide-1 receptor (GLP1R) agonists have been shown to reduce major cardiovascular events in diabetic patients, but their role in heart failure (HF) remains controversial. Recent evidence implies their potential benefits on cardiometabolism such as lipid metabolism, which may contribute to lowering the risk of HF. Consequently, we designed a Mendelian randomization (MR) study to investigate the causal relationships of circulating lipids mediating GLP1R agonists in HF.MethodsThe available cis-eQTLs for GLP1R target gene were selected as instrumental variables (IVs) of GLP1R agonism. Positive control analyses of type 2 diabetes mellitus (T2DM) and body mass index (BMI) were conducted to validate the enrolled IVs. Two-sample MR was performed to evaluate the associations between GLP1R agonism and HF as well as left ventricular ejection fraction (LVEF). Summary data for HF and LVEF were obtained from two genome-wide association studies (GWASs), which included 977,323 and 40,000 individuals of European ancestry, respectively. The primary method employed was the random-effects inverse variance weighted, with several other methods used for sensitivity analyses, including MR-Egger, MR PRESSO, and weighted median. Additionally, multivariable MR and mediation MR were applied to identify potentially causal lipid as mediator.ResultsA total of 18 independent IVs were included. The positive control analyses showed that GLP1R agonism significantly reduced the risk of T2DM (OR = 0.79, 95% CI = 0.75–0.85, p < 0.0001) and decreased BMI (OR = 0.95, 95% CI = 0.93–0.96, p < 0.0001), ensuring the effectiveness of selected IVs. We found favorable evidence to support the protective effect of GLP1R agonism on HF (OR = 0.75, 95% CI = 0.71–0.79, p < 0.0001), but there was no obvious correlation with increased LVEF (OR = 1.01, 95% CI = 0.95–1.06, p = 0.8332). Among the six blood lipids, only low-density lipoprotein cholesterol (LDL-C) was both associated with GLP1R agonism and HF. The causal effect of GLP1R agonism on HF was partially mediated through LDL-C by 4.23% of the total effect (95% CI = 1.04–7.42%, p = 0.0093).ConclusionsThis study supported the causal relationships of GLP1R agonists with a reduced risk of HF. LDL-C might be the mediator in this association, highlighting the cardiometabolic benefit of GLP1R agonists on HF.Graphical

Mendelian randomization did not support the causal effect of diabetes on aortic diseases.

Observational studies revealed paradoxically inverse associations between diabetes and aortic diseases (aortic aneurysm or aortic dissection), yet the causality remains to be determined. To investigate the causal associations between diabetes and aortic diseases using Mendelian randomization (MR) analyses. Summary-level data for exposures (type 1 diabetes, type 2 diabetes, fasting glucose, fasting insulin, glycated hemoglobin) and outcomes (aortic dissection and aortic aneurysm) were obtained from public genome-wide association study data. The principal analysis was the inverse-variance weighted (IVW) method. Sensitivity analyses were also carried out, including weighted median, MR-Egger, and multivariable MR methods. According to IVW results, type 1 diabetes (odds ratio [OR]: 0.99; 95% confidence interval [CI] 0.93-1.07; P = 0.87), type 2 diabetes (OR: 0.97; 95% CI 0.77-1.20; P = 0.75), fasting glucose (OR: 1.16; 95% CI 0.48-2.84; P = 0.74), fasting insulin (OR: 2.75; 95% CI 0.53-14.26; P = 0.23), or glycated hemoglobin (OR: 0.33; 95% CI 0.09-1.17; P = 0.09) had no causal effect on aortic dissection. Similarly, type 1 diabetes, type 2 diabetes, fasting glucose, fasting insulin, or glycated hemoglobin had no causal effect on aortic aneurysm. Sensitivity analyses revealed consistent results. MR-Egger method and funnel plot yielded no indication of directional pleiotropy. Diabetes had no causal associations with aortic dissection or aortic aneurysm. The observed inverse associations in previous cohort studies may be explained by confounding factors or reverse causation.

Genetic associations of birthweight, childhood, and adult BMI with metabolic dysfunction-associated steatotic liver disease: a Mendelian randomization

PurposeThe causal relationship between life course adiposity with metabolic dysfunction-associated steatotic liver disease (MASLD) is ambiguous. We aimed to investigate whether there is an independent genetic causal relationship between body size at various life course and MASLD.MethodsWe performed univariable and multivariable Mendelian randomization (MR) to estimate the causal effect of body size at different life stages on MASLD (i.e., defined by the clinical comprehensive diagnosis from the electronic health record [HER] codes [ICD9/ICD10] or diagnostic phrases), including birthweight, childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), body fat percentage (BFP).ResultsIn univariate analyses, higher genetically predicted lower birthweight (ORIVW = 0.61, 95%CI, 0.52 to 0.74), Childhood BMI ( ORIVW = 1.37, 95%CI, 1.12 to 1.64), and adult BMI (ORIVW = 1.41, 95%CI, 1.27 to 1.57) was significantly associated with subsequent risk of MASLD after Bonferroni correction. The MVMR analysis demonstrated compelling proof that birthweight and adult BMI had a direct causal relationship with MASLD. However, after adjusting for birthweight and adult BMI, the direct causal relationship between childhood BMI and MASLD disappeared.ConclusionFor the first time, this MR elucidated new evidence for the effect of life course adiposity on MASLD risk, providing lower birthweight and duration of obesity are independent risk factors for MASLD. Our findings indicated that weight management during distinct time periods plays a significant role in the prevention and treatment of MASLD.

Differential white blood cell count and epigenetic clocks: a bidirectional Mendelian randomization study

BackgroundHuman aging and white blood cell (WBC) count are complex traits influenced by multiple genetic factors. Predictors of chronological age have been developed using epigenetic clocks. However, the bidirectional causal effects between epigenetic clocks and WBC count have not been fully examined.MethodsThis study employed Mendelian randomization (MR) to analyze summary statistics from four epigenetic clocks involving 34,710 participants, alongside data from the Blood Cell Consortium encompassing 563,946 individuals. We primarily explored bidirectional causal relationships using the random-effects inverse-variance weighted method, supplemented by additional MR methods for comprehensive analysis. Additionally, multivariate MR was applied to investigate independent effects of WBC count on epigenetic age acceleration.ResultsIn the two-sample univariate MR (UVMR) analysis, we observed that a decrease in lymphocyte count markedly accelerated aging according to the PhenoAge, GrimAge, and HannumAge metrics (all P < 0.01, β < 0), though it did not affect Intrinsic Epigenetic Age Acceleration (IEAA). Conversely, an increase in neutrophil count significantly elevated PhenoAge levels (β: 0.38; 95% CI 0.14, 0.61; P = 1.65E−03 < 0.01). Reverse MR revealed no significant causal impacts of epigenetic clocks on overall WBC counts. Furthermore, in multivariate MR, the impact of lymphocyte counts on epigenetic aging metrics remained statistically significant. We also identified a marked causal association between neutrophil counts and PhenoAge, GrimAge, and HannumAge, with respective results showing strong associations (PhenoAge β: 0.78; 95% CI 0.47, 1.09; P = 8.26E−07; GrimAge β: 0.55; 95% CI 0.31, 0.79; P = 5.50E−06; HannumAge β: 0.42; 95% CI 0.18, 0.67; P = 6.30E−04). Likewise, eosinophil cell count demonstrated significant association with HannumAge (β: 0.33; 95% CI 0.13, 0.53; P = 1.43E−03 < 0.01).ConclusionThese findings demonstrated that within WBCs, lymphocyte and neutrophil counts exert irreversible and independent causal effects on the acceleration of PhenoAge, GrimAge, and HannumAge. Our findings highlight the critical role of WBCs in influencing epigenetic clocks and underscore the importance of considering immune parameters when interpreting epigenetic age.

A Multivariable Mendelian Randomization Study of Systolic and Diastolic Blood Pressure, Lipid Profile, and Heart Failure Subtypes.

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressures and lipids on HF subtypes. Genetic instruments for blood pressures and lipids were derived from genome-wide association studies (GWASs) among the European participants of the UK Biobank. GWAS summaries of HFrEF and HFpEF were obtained from the meta-analysis of the European participants from the Million Veteran Program and the Vanderbilt University DNA Databank. Systolic blood pressure exhibited a supportive MR association primarily with HFpEF (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.04-1.23), while diastolic blood pressure had an independent MR association with HFrEF (OR, 1.43; 95% CI, 1.13-1.77). MR associations also supported the observation that higher levels of low-density lipoprotein cholesterol increase the risk for both subtypes (HFrEF OR, 1.10 and 95% CI, 1.05-1.17; HFpEF OR, 1.05 and 95% CI, 1.02-1.09). These findings underscore differences in HF subtype-specific risk profiles and mechanisms, which may lead to different interventional strategies for different HF subtypes.

Mendelian randomization analysis reveals the combined effects of epigenetics and telomere biology in hematologic cancers

BackgroundTelomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks.MethodsThis study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR).ResultsOur research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007).ConclusionThe study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.

Is there a causal relationship between resistin levels and bone mineral density, fracture occurrence? A mendelian randomization study.

In a great many of observational studies, whether there is a relevance of resistin levels on bone mineral density (BMD) and fracture occurrence has been inconsistently reported, and the causality is unclear. We aim to assess the resistin levels on BMD and fracture occurrence within a Mendelian randomization (MR) analysis. Exposure and outcome data were derived from the Integrative Epidemiology Unit (IEU) Open genome wide association studies (GWAS) database. Screening of instrumental variables (IVs) was performed subject to conditions of relevance, exclusivity, and independence. Inverse variance weighting (IVW) was our primary method for MR analysis based on harmonized data. Weighted median and MR-Egger were chosen to evaluate the robustness of the results of IVW. Simultaneously, heterogeneity and horizontal pleiotropy were also assessed and the direction of potential causality was detected by MR Steiger. Multivariable MR (MVMR) analysis was used to identify whether confounding factors affected the reliability of the results. After Bonferroni correction, the results showed a suggestively positive causality between resistin levels and total body BMD (TB-BMD) in European populations over the age of 60 [β(95%CI): 0.093(0.021, 0.165), P = 0.011]. The weighted median [β(95%CI): 0.111(0.067, 0.213), P = 0.035] and MR-Egger [β(95%CI): 0.162(0.025, 0.2983), P = 0.040] results demonstrate the robustness of the IVW results. No presence of pleiotropy or heterogeneity was detected between them. MR Steiger supports the causal inference result and MVMR suggests its direct effect. In European population older than 60 years, genetically predicted higher levels of resistin were associated with higher TB-BMD. A significant causality between resistin levels on BMD at different sites, fracture in certain parts of the body, and BMD in four different age groups between 0-60 years of age was not found in our study.

Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common. To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR). This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024. Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices. Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control. The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 β-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective β estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP. The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

Associations Between Gut Microbiota and Alcohol Abuse: A Mendelian Randomisation and Bioinformatics Study.

Alcohol abuse, also known as Alcohol Use Disorder (AUD), is a substance dependency psychiatric disorder. We aimed to establish a causal relationship between specific gut microbiota and alcohol abuse using Mendelian Randomisation (MR) and bioinformatics methods. We acquired summary data of genome-wide association studies (GWAS) for gut microbiota and alcohol abuse from the Mibiogen and Finngen databases, respectively. We conducted MR analyses using various methodologies and mapped the single nucleotide polymorphisms (SNPs) to genes via the FUMA GWAS platform. We further performed multiple enrichment analyses and a Multi-variable Mendelian Randomisation (MVMR) approach to examine whether gut microbiota influences alcohol abuse by modulating neurotransmitter-related amino acids. The MR analysis revealed an inverse relationship between the genus Eubacterium ventriosum group and the Porphyromonadaceae family with alcohol abuse. Gene enrichment analysis showed that these genes are expressed in brain tissue and are involved in addictive disorders, psychiatric conditions, immunological processes, neurotransmitter synthesis and synaptic regulation. MVMR analysis suggested that the Porphyromonadaceae family as well as genus Eubacterium ventriosum group may suppress alcohol abuse through the metabolism of neurotransmitter-related amino acids, especially Tryptophan. The MR analysis and bioinformatics investigations indicate that the genus Eubacterium ventriosum group and Porphyromonadaceae family confer a protective effect against alcohol abuse, potentially through the modulation of synaptic function.

Unraveling the impact of irritability on esophageal diseases: Insights from multivariable Mendelian randomization analysis

BackgroundPrevious studies have suggested a potential association between irritability and the risk of various diseases. However, establishing a causal relationship has remained a significant challenge. To address this issue, we employed Mendelian randomization (MR), a sophisticated approach that leverages genotype data to emulate the conditions of randomized controlled trials. This method enables us to investigate the potential causal link between irritability and the susceptibility to esophageal diseases. MethodsWe conducted an extensive multivariable MR analysis using summary-level data from genome-wide association studies (GWAS) encompassing various esophageal diseases, including gastroesophageal reflux disease (GERD), esophageal cancer (EC), and Barrett's esophagus. Both univariable and multivariable MR analyses were performed to elucidate and confirm the causal association between genetically predicted irritability and the incidence of esophageal diseases. ResultsBased on our primary causal effects model utilizing MR analyses with the inverse-variance weighted (IVW) method, genetically predicted irritability was identified as a risk factor for GERD (OR = 2.413; 95 % CI: 1.678–3.470; P = 2.03E-06) and Barrett's esophagus (OR = 2.306; 95 % CI: 1.042–5.101; P = 0.039). However, irritability was not found to be associated with the risk of EC, even after adjusting for BMI, smoking initiation, and alcohol consumption. ConclusionThe multivariable MR analysis performed in this study demonstrated a causal relationship between irritability and esophageal diseases. It is imperative to acknowledge the need for further large-scale prospective studies to validate these findings.