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PubMed2005

Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach.

Mendelian randomization, the use of common polymorphisms as surrogates for measuring exposure levels in epidemiologic studies, provides one method of assessing the causal nature of some environmental exposures. This can be illustrated by looking at the association between the ALDH2 polymorphism and esophageal cancer. Alcohol drinking is considered a risk factor for esophageal cancer, and exposure to high levels of acetaldehyde, the principal metabolite of alcohol, may be responsible for the increased cancer risk. The ability to metabolize acetaldehyde is encoded by the ALDH2 gene, which is polymorphic in some populations. The ALDH2*2 allele produces an inactive protein subunit, which is unable to metabolize acetaldehyde. An individual's genotype at this locus may influence their esophageal cancer risk through two mechanisms, first through influencing alcohol intake and second through influencing acetaldehyde levels. We have carried out a meta-analysis of studies looking at the ALDH2 genotype and esophageal cancer and found that risk was reduced among *2*2 homozygotes [odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.16-0.80] and increased among heterozygotes (OR, 3.19; 95% CI, 1.86-5.47) relative to *1*1 homozygotes. This provides strong evidence that alcohol intake increases the risk of esophageal cancer and individuals whose genotype results in markedly lower intake, because they have an adverse reaction to alcohol are thus protected. This meta-analysis also provides evidence that acetaldehyde plays a carcinogenic role in esophageal cancer. The two different processes operating as a result of the ALDH2 genotype have implications for the interpretation of studies using the Mendelian randomization paradigm.

Acetaldehyde↗
PubMed2026

The causal effect of family history of cardiovascular disease on erectile dysfunction: a randomized clinical study and Mendelian randomization study.

Erectile dysfunction (ED) is increasingly recognized as an early clinical marker of cardiovascular disease (CVD); however, the causal role of familial predisposition to CVD in ED development remains insufficiently defined. This study investigated whether genetic susceptibility associated with a parental history of CVD exerts a causal influence on ED risk, integrating clinical data with Mendelian randomization (MR) analysis. A cohort of 288 men who attended the Department of Andrology of Xiangya Hospital (Changsha, China) between June 2017 and June 2023 were recruited, comprising 223 patients with clinically confirmed ED and 65 controls. Detailed demographic, cardiovascular, and ED severity data were collected. Genetic variants associated with ED and parental CVD history were obtained from genome-wide association study (GWAS) summary statistics, and two-sample MR analyses were conducted to evaluate causal effects. Clinically, men with ED were significantly older, exhibited higher body mass index (BMI), and demonstrated lower testosterone levels compared with controls. A trend toward an association between family history of CVD and ED was observed. MR analyses provided robust evidence of causality, with paternal CVD history increasing ED risk and maternal CVD history exerting an even stronger effect. Sensitivity analyses confirmed the stability of these findings without evidence of pleiotropic bias. Collectively, these results indicate that familial genetic susceptibility to CVD independently contributes to the risk of ED. These findings underscore the clinical importance of incorporating family history into ED risk stratification and highlight the need for early screening and preventive strategies in men with a family history of CVD. Proactive management of this high-risk population may mitigate the future burden of ED and its cardiovascular sequelae.

Humans↗
PubMed2026

Reassessing Instrument Strength in Two-Sample Mendelian Randomization Analysis.

Mendelian randomization (MR) analysis is widely used to estimate causal relationships between risk factors and outcomes of interest. Two-sample MR approaches have gained increasing attention in genetic epidemiology due to the growing availability of Genome-Wide Association Study (GWAS) summary statistics from public databases. A critical step in two-sample MR is the selection of genetic variants as instrumental variables (IVs). Although genome-wide significant variants are typically preferred, the inclusion of variants with weaker association p-values is considered, as they may potentially improve power through an increased instrument number of instruments, while they may introduce weak instrument bias and attenuate effect estimates towards the null. Our simulation results show that even modest levels of pleiotropy substantially increase the variability of causal effect estimates, while the inclusion of weak IVs does not substantially affect the direction and variability of causal effect estimates in most cases. In real data analyses, we used two released versions of FinnGen GWAS summary statistics with different sample sizes as exposure GWASs to assess the influence of weak IVs. Here, the inclusion of IVs with higher exposure-association p-values resulted in weakened estimated effect sizes, particularly when the exposure GWAS sample size was small. These findings suggest that incorporating weak IVs is reasonable when the exposure GWAS sample size is large, but it poses a risk of falsely concluding null associations when the exposure GWAS sample size is small.

Journal Article↗
PubMed2006

Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials.

"Mendelian randomization" refers to the random assortment of genes transferred from parent to offspring at the time of gamete formation. This process has been compared to a randomized controlled trial of genetic variants. This could greatly aid observational epidemiology by potentially allowing an unbiased estimate of the effects of gene products on disease outcomes. However, studies utilizing Mendelian randomization to estimate effects of gene products on outcomes should be interpreted with caution. In this paper, the authors discuss some of the challenges facing epidemiologists in the analysis and interpretation of Mendelian randomization studies, particularly those that become apparent when the analogy with randomized controlled trials is closely examined. The authors conclude that Mendelian randomization is a powerful addition to etiologic research tools. However, care must be taken, because drawing valid causal inferences from its application depends upon more extensive assumptions than are required in randomized controlled trials.

Causality↗
PubMed2026

A flexible framework for robust and efficient Mendelian randomization with debiasing.

Mendelian randomization (MR) has been widely used to infer causal relationships between exposures and outcomes in epidemiological studies. However, classical MR assumptions can be violated when genetic variants are associated with outcomes through pathways other than the exposure, leading to uncorrelated and/or correlated pleiotropy. Additionally, measurement error arising from the inherent uncertainty in summary statistics obtained from large-scale genome-wide association studies can introduce bias into the causal effect estimate. To address these issues, we develop a debiased mixture inverse variance weighting ($\mathsf{dmIVW}$) method with three major advantages. First, it is capable of simultaneously handling various types of pleiotropy and eliminating the bias caused by uncertainty. Second, it can guard against distortion caused by invalid genetic variants while effectively harnessing their information. Third, our unified framework facilitates a fair comparison and combination of a series of submodels, encompassing several popular MR methods as special cases. Through real data applications, the effectiveness and robustness of $\mathsf{dmIVW}$ in estimating the causal effects of risk factors on common diseases are demonstrated.

Mendelian Randomization Analysis↗
PubMed2026

Exploring the role of gut microbiota in coronary atherosclerosis through lipoprotein-mediated cholesterol transport and distribution: A Mendelian randomization analysis.

We employed Mendelian randomization (MR) to explore causal relationships between gut microbiota (GM), coronary atherosclerotic heart disease (CAHD), and potential metabolic mediators. We utilized summary statistics from genome-wide association studies (GWAS), encompassing data on 473 GM traits from comprehensive microbiome GWAS, 61 lipoprotein-mediated cholesterol transport and distribution data from large-scale metabolic biomarker studies, and coronary atherosclerosis (CA) data from the GWAS catalog (study accession GCST90043957) involving 456,348 European participants. Bidirectional MR analyses were conducted to investigate the causal relationships between GM and CA. Two-sample Mendelian randomization analyses were performed to identify potential mediating metabolites and quantify the mediation proportion. Ultimately, the GM GCA-900066755, identified through MR as having a potential causal relationship, was selected to investigate its potential effects on CA by influencing cholesterol transport and distribution. Our results indicated that GCA-900066755 was positively associated with an increased risk of CA (odds ratio = 1.156). CA did not significantly affect the levels of GCA-900066755 (odds ratio = 1.009). GCA-900066755 was negatively correlated with total cholesterol levels in medium high-density lipoprotein, which reduced CA risk, and was positively correlated with total cholesterol levels in low-density lipoprotein (LDL), large LDL, medium LDL, and small LDL, which were positively associated with CA. Mediation analysis showed 7 data points mediating the association between GCA-900066755 and CA. Our MR study supports a causal relationship between specific GM groups and the risk of CAHD, highlighting that cholesterol traits are not merely outcomes associated with the relationship between GM and CAHD, but are important mediating factors. Understanding the biological mechanisms of these traits can provide a concrete foundation for future targeted interventions.

Mendelian Randomization Analysis↗
PubMed2004

An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization.

A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person's genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure. Plotting the log odds ratio of genotype-disease against the mean genotype-phenotype difference may help investigators detect departures from the assumptions underlying Mendelian randomization. Testing for differences between studies reporting on only the genotype-phenotype or genotype-disease association and those reporting on both associations may help in detecting reporting bias. This integrated approach to the meta-analysis of genotype-phenotype and genotype-disease studies is illustrated here using the example of the methylenetetrahydrofolate reductase (MTHFR) gene, homocysteine level, and coronary heart disease. An integrated meta-analytical approach may increase the precision of this estimate and provide information on the assumptions underlying Mendelian randomization. Serious biases may arise if the assumptions behind the analysis based on Mendelian randomization are not met.

Confidence Intervals↗
PubMed2026

Assessing the Association Between Age at First Sexual Intercourse and HIV Infection Risk Using A Two-sample Mendelian Randomization Framework.

This study applied a two-sample Mendelian randomization framework to investigate the potential association between age at first sexual intercourse (AFS) and the risk of Human Immunodeficiency Virus (HIV) infection. Summary-level Genome-Wide Association Study (GWAS) data from European populations were analyzed, including 214,547 individuals for AFS and 357 HIV cases with 218,435 controls from the FinnGen R5 dataset. Independent single-nucleotide polymorphisms significantly associated with AFS were selected as instrumental variables following linkage disequilibrium clumping and instrument-strength assessment. Causal estimates were evaluated using inverse-variance weighting (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode. Cochran's Q test, MR-Egger intercept analysis, MR-PRESSO assessment, and leave-one-out sensitivity analyses were performed to evaluate heterogeneity, pleiotropy, and robustness. The IVW analysis suggested that genetically predicted later AFS was associated with reduced HIV infection risk (OR = 0.192, 95% CI = 0.062-0.592, P = 0.004), whereas earlier sexual debut corresponded to increased HIV susceptibility. Directionally consistent findings across multiple Mendelian randomization methods supported the stability of the observed association. However, the findings should be interpreted cautiously because the HIV outcome analysis relied on a single dataset with a limited number of HIV cases. These results support a potential association between earlier sexual debut and HIV susceptibility and demonstrate the utility of Mendelian randomization for investigating behavioral risk factors associated with infectious disease outcomes.

Humans↗
PubMed2025

Validation of breast cancer as a risk factor for anxiety and depression: Insights from Mendelian randomization analysis.

This study employed Mendelian randomization (MR) analysis to confirm the association between breast cancer and the risk of anxiety and depression, and to explore the molecular mechanisms by which lipid nanoparticles of ketamine (LNP@Ket) modulate these behaviors in a mouse model of breast cancer. Through single-cell transcriptomic analysis, the study aimed to clarify nuclear factor erythroid 2-related factor 2 (Nrf2)'s role in the development of anxiety and depression in these mice. Analysis of patient data from genome-wide association study (GWAS) databases supported the link between breast cancer, anxiety, and depression. In vivo experiments demonstrated that treating breast cancer mice with LNP@Ket significantly reduced anxiety and depression behaviors. The synthesis of LNP@Ket and its subsequent analysis highlighted its inhibitory effects on these behaviors. Single-cell transcriptomic sequencing identified key cells and genes affected by LNP@Ket treatment, particularly emphasizing Nrf2. Upregulation of Nrf2 in astrocytes increased the expression of antioxidant enzymes and reduced pro-inflammatory cytokines, alleviating anxiety and depression symptoms by inhibiting neuroinflammation and neurodegeneration. This comprehensive study highlights the pivotal role of Nrf2 in the therapeutic efficacy of LNP@Ket for treating anxiety and depression in breast cancer mice.

Anxiety and depression behaviors↗
PubMed2024

Causal effect of the age at first birth with depression: a mendelian randomization study.

BACKGROUND: This study aimed to explore the causal relationship between age at first birth (AFB) and depression. METHODS: Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result. RESULTS: We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793&#x2009;-&#x2009;0.861; P&#x2009;=&#x2009;4.51&#x2009;&#xd7;&#x2009;10-&#x2009;20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P&#x2009;<&#x2009;0.05). During the sensitivity analysis, the heterogeneity test (Q-value&#x2009;=&#x2009;55.061, df&#x2009;=&#x2009;48, P&#x2009;=&#x2009;2.81&#x2009;&#xd7;&#x2009;10-&#x2009;01, I2&#x2009;=&#x2009;12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept&#x2009;=&#x2009;8.932&#x2009;&#xd7;&#x2009;10-&#x2009;3. SE&#x2009;=&#x2009;6.909&#x2009;&#xd7;&#x2009;10-&#x2009;3. P&#x2009;=&#x2009;2.02&#x2009;&#xd7;&#x2009;10-&#x2009;01) and MR_PRESSO global test (P&#x2009;=&#x2009;2.03&#x2009;&#xd7;&#x2009;10-&#x2009;01) indicated there is no pleiotropy. CONCLUSION: There is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.

Humans↗
PubMed2006

Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization'.

BACKGROUND: Blood concentrations of fibrinogen have been associated with coronary heart disease risk in epidemiological studies, but it is uncertain whether this association is causal or reflects residual confounding by other risk factors. We investigated the relationship between the single nucleotide polymorphism at position -148 in the beta-fibrinogen gene promoter (beta - 148C/T), blood fibrinogen levels, and risk of myocardial infarction (MI) in sufficiently large numbers of coronary disease cases to reliably address this question. METHODS: Genotyping and measurement of blood fibrinogen concentration were carried out in 4,685 cases of confirmed MI and 3,460 controls with no history of coronary disease. A meta-analysis of ISIS and 19 other studies of beta-fibrinogen genotypes involving a total of 12,220 coronary disease cases and 18,716 controls was conducted. RESULTS: Among the ISIS controls, mean plasma fibrinogen concentrations with the C/C, C/T and T/T genotypes were 3.34 (SE 0.015), 3.48 (0.022), and 3.60 (0.064) g/l, respectively, corresponding to an increase of 0.14 (0.024) g/l per T allele (trend P < 0.0001). In the case-control comparison, 0.14 g/l higher usual plasma fibrinogen concentration was associated with an age-adjusted and sex-adjusted risk ratio for MI of 1.17 [95% confidence interval (95% CI) 1.14-1.19; P < 0.0001]. But, after further adjustment for smoking, body mass index, and plasma apolipoprotein B/A(1) ratio, this risk ratio fell to 1.03 (95% CI 1.00-1.05; P = 0.05). Moreover, fibrinogen genotype was not significantly associated with MI incidence: risk ratio of 1.06 (95% CI 0.96-1.16) per higher-fibrinogen allele in ISIS alone and of 1.00 (95% CI 0.95-1.04) per allele in the meta-analysis. CONCLUSIONS: Genotypes that produce lifelong differences in fibrinogen concentrations do not materially influence coronary disease incidence. As these genotype-dependent differences in fibrinogen were allocated randomly at conception (Mendelian randomization), this association is not likely to be confounded by other factors. Consequently, these genetic results provide strong evidence that long-term differences in fibrinogen concentrations are not a major determinant of coronary disease risk.

Adult↗
PubMed2024

Reassessing the Association of Sedentary Behavior and Physical Activity with Ischemic Stroke: A Mendelian Randomization Study.

PURPOSE: Findings from previous Mendelian randomization (MR) studies disagreed with the current scientific consensus regarding the role of physical activity (PA) and sedentary behavior in ischemic stroke (IS). We reassessed these associations with a focus on etiological subtypes of IS and the potential mediating roles of cardiometabolic traits and brain imaging-derived phenotypes (IDPs). METHODS: We performed MR analyses using summary statistics from genome-wide association studies of sedentary behavior and PA ( n = 88,411 ~ 608,595), cardiometabolic traits ( n = 393,193 ~ 694,649), brain IDPs ( n = 33,224), and the latest IS data (62,100 cases and 1,234,808 controls). Inverse-variance weighted regression was used as the primary method, complemented by several sensitivity analyses. A two-step MR approach was employed to assess the mediating effects of cardiometabolic traits and brain IDPs. RESULTS: Genetic liability to leisure-time moderate-to-vigorous PA (MVPA) and higher overall PA (OPA) were associated with reduced risks of IS and small vessel stroke (Benjamini-Hochberg adjusted P < 0.05). Suggestive associations were observed between longer leisure-screen time and higher IS risk and between higher OPA and lower cardioembolic stroke risk ( P < 0.05). The isotropic volume fraction in the anterior limb of the left internal capsule, as well as some cardiometabolic metrics, partially mediated these associations. There was no evidence for causal effects of overall MVPA, overall light-intensity PA, or overall sedentary duration on IS. CONCLUSIONS: Longer leisure screen time, less OPA, and not engaging in MVPA during leisure time were associated with higher risk of IS. The associations between PA and IS depended on different subtypes and were mediated by changes in anterior limb of the left internal capsule and cardiometabolic biomarkers.

Humans↗
PubMed2026

Genetically predicted lower FLT3L levels increase the risk of hypertrophic cardiomyopathy partly mediated by phosphate: Evidence from a 2-step Mendelian randomization analysis.

We performed a 2-step Mendelian randomization (MR) study to investigate the associations of Fms-related tyrosine kinase 3 ligand (FLT3L) and phosphate levels with the risk of hypertrophic cardiomyopathy (HCM). Genetic instruments for 75 circulating inflammatory factors were obtained from the NHGRI-EBI GWAS Catalog, while summary statistics for circulating phosphate and HCM were derived from the UK Biobank and FinnGen, respectively. Univariable MR analysis using the inverse-variance weighted method indicated that genetically predicted higher phosphate levels were associated with an increased risk of HCM (OR&#x2005;=&#x2005;1.36, P&#x2005;=&#x2005;4.82&#x2005;&#xd7;&#x2005;10-2). Among the inflammatory markers, FLT3L emerged as a significant candidate and showed inverse associations with phosphate levels (&#x3b2;&#x2005;=&#x2005;-0.05, P&#x2005;=&#x2005;1.70&#x2005;&#xd7;&#x2005;10-9) and HCM (OR&#x2005;=&#x2005;0.79, P&#x2005;=&#x2005;4.10&#x2005;&#xd7;&#x2005;10-2). Bidirectional MR analyses did not support a causal effect of phosphate on FLT3L. Mediation analysis suggested that phosphate levels accounted for an estimated 12.05% of the total effect of FLT3L on HCM. Genetic liability to lower FLT3L levels is associated with a higher risk of HCM, and this relationship may be partially mediated through circulating phosphate levels.

Humans↗
PubMed2026

Association between 1400 blood metabolites and the risk of ankylosing spondylitis: A 2-stage, 2-sample Mendelian randomization study.

Human blood metabolites have been closely linked to ankylosing spondylitis (AS) in observational studies, yet direct causal evidence remains limited. This study aims to use Mendelian randomization (MR) to pinpoint causal metabolites associated with AS and to predict potential side effects of metabolite interventions. Genetic instruments for exposure were sourced from a genome-wide association study of 1400 blood metabolites, while genome-wide association study data for AS outcomes were derived from the FinnGen cohort. The primary MR analysis was conducted using the inverse variance weighted method. Supplemental analyses were conducted using weighted median, MR-Egger, simple mode, and weighted mode methods, while sensitivity analyses were performed to evaluate heterogeneity and pleiotropy. A replication analysis using an additional the UK Biobank cohort was also performed to determine metabolites associated with AS. The Steiger test and linkage disequilibrium score regression were used to further strengthen causal inference. Lastly, a phenome-wide Mendelian randomization analysis was performed to investigate the potential on-target side effects of metabolite interventions. After comprehensive analyses, 3 metabolites (the 2'-deoxyuridine levels, the hate to mannose ratio, and the Uridine to 2'-deoxyuridine ratio) were identified as being genetically associated with AS. The phenome-wide Mendelian randomization analysis revealed that the hate to mannose ratio might have deleterious effects on 4 other diseases, while no significant associations were found for the 2'-deoxyuridine levels or the uridine to 2'-deoxyuridine ratio with other diseases. This systematic MR analysis unveiled the potential role of the 2'-deoxyuridine levels, hate to mannose ratio and uridine to 2'-deoxyuridine ratio as the causal mediator in the development of AS. Considering the advantages and disadvantages, 2'-deoxyuridine appears as the most promising prospective therapeutic target for the prevention of AS.

Humans↗
PubMed2026

HNRNPC as a Novel Therapeutic Target for Ischemic Heart Disease: Evidence From Mendelian Randomization and Experimental Validation.

BACKGROUND: Several studies have suggested that N6-methyladenosine (m6A) plays an essential role in cardiovascular disease, but the causality of m6A on ischemic heart disease (IHD) remains unknown. Therefore, this study investigated the potential relationship between m6A and IHD using a 2-sample Mendelian randomization method. METHODS: The publicly available genome-wide association study data for m6A-related proteins were obtained from the INTERVAL study, a large population-based cohort of healthy blood donors in the United Kingdom, whereas the genome-wide association study database (including 30&#x2009;952 cases and 187&#x2009;840 healthy controls) provided the IHD data. We performed a 2-sample Mendelian randomization analysis to evaluate the potential causal association between HNRNPC (heterogeneous nuclear ribonucleoprotein C) and IHD, followed by experimental validation in&#xa0;vitro and in&#xa0;vivo to confirm the role of HNRNPC in IHD pathogenesis. RESULTS: There was no indication of pleiotropy or heterogeneity among the 6 m6A-associated proteins, but Mendelian randomization analysis revealed that HNRNPC (odds ratio [OR], 0.93 [95% CI, 0.88-0.97]; P=0.002) was associated with IHD. When IHD developed, there was a significant upregulation of HNRNPC expression in both animal and cellular tests. HNRNPC knockdown prevented oxidative stress, mitochondrial dysfunction, and cell death. CONCLUSIONS: The Mendelian randomization study suggests a potential causal association of the m6A-related protein HNRNPC in the cause of IHD and verified the accuracy of the results through a series of experiments, which will help us understand the pathogenesis of IHD and identify potential therapeutic targets in the future.

Humans↗
PubMed2025

EP300-mediated lactylation leads to ulcerative colitis via CD86-positive plasmacytoid dendritic cells: A Mendelian randomization and mediation analysis.

This study explores the potential mechanism between lactylation and ulcerative colitis (UC) using two-sample Mendelian randomization and multi-omics analysis. This study employed expression quantitative trait loci and protein quantitative trait loci as exposures, with UC from the Finnish database as the outcome, to conduct Mendelian randomization analysis on lactylation-related target genes, aiming to investigate the causal relationships between these exposures and the outcome. Sensitivity and pleiotropy tests, combined with colocalization analysis, are performed to identify the best target genes and ensure the robustness of the results. Finally, immune cells are included for mediation analysis between lactylation and UC to explore potential mechanisms of action. Through Mendelian randomization analysis combined with sensitivity and pleiotropy tests, 2 lactylation target genes were found to have a significant causal relationship with UC. Subsequent colocalization analysis confirmed EP300 as a potential gene target. After including immune cells in the mediation analysis, it was discovered that there is a potential mechanism involving EP300, CD86+ plasmacytoid dendritic cells (pDCs), and UC. There is a significant causal relationship between lactylation and UC. Furthermore, the lactylation-modified gene EP300 may lead to UC occurrence by regulating CD86+ pDCs.

Humans↗
PubMed2025

No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.

Mendelian randomization (MR) is increasingly used in epidemiological studies to investigate causal relationships. MR depends on 3 fundamental instrumental variable assumptions: relevance, independence, and exclusion restriction. Studies often assume that MR mitigates bias from confounding due to the random allocation of genetic variants at conception. In this perspective, using causal directed acyclic graphs, we discuss several scenarios where biases in MR analyses may arise due to the nature of the data or methods being used. These include (1) collider bias due to the nonrandom selection of participants into study populations used for conducting genome-wide association studies (GWAS), (2) indirect genetic effects arising from population-based GWAS rather than within-family studies, and (3) collider bias due to gene-environment interaction effects on the exposure in nonlinear MR analyses. We provide practical considerations for examining and reducing these biases in MR analyses.

Humans↗
PubMed2026

Investigation of the Causal Association Between Biological Aging Indicators and Vascular Disease Through Two-Sample Mendelian Randomization Analysis.

ObjectiveThis study used two-sample Mendelian Randomization to investigate the causal link between multiple biological aging indicators and vascular disease.MethodsSummary genetic data was obtained from genome-wide association studies (GWAS) focusing on aging-related exposures and various vascular disease outcomes. The exposures included granulocyte proportions, PAI-1 (plasminogen activator inhibitor-1), telomere lengths, and the Frailty Index. The primary analysis employed the Inverse Variance Weighted (IVW) method to estimate causal relationships, supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran's Q test, MR-Egger regression, leave-one-out test, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test, were conducted to evaluate heterogeneity and pleiotropy.ResultsThe analysis revealed distinct pathways after sensitivity adjustments. A higher genetically predicted Frailty Index was associated with an increased risk of abdominal aortic aneurysm (OR=2.5935, 95% CI: 1.3936-4.8268, P=0.0026, false discovery rate (FDR)=0.0475), atherosclerosis excluding cerebral and coronary sclerosis (OR=2.0262, 95% CI:1.5179-2.705, P=1.66&#xd7;10-6, FDR=1&#xd7;10-4), and arterial thromboembolic events (OR = 4.0306, 95% CI: 1.7133-9.4818, P = 0.0014, FDR = 0.0337). Conversely, longer telomere length demonstrated a strong, specific protective effect against abdominal aortic aneurysm (OR=0.5008, 95% CI:0.4111-0.6100, P=6.42&#xd7;10-12, FDR=9.25&#xd7;10-10), indicating that shorter telomere length is associated with an increased risk of AAA. Furthermore, a lower granulocyte proportion was causally linked to an increased risk of thoracic aortic aneurysm (OR=0.0181, 95% CI: 0.0014-0.2376, P=0.0023, FDR=0.0465).ConclusionThis study identifies three genetic pathways linking biological aging to vascular disease, offering new molecular targets for its prevention and treatment.

Humans↗