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PubMed2026

Integrated single-cell RNA sequencing and mendelian randomization analysis identifies causal immune-related driver genes in the heart failure inflammatory microenvironment.

BACKGROUND: Heart failure (HF) is a major global cause of cardiovascular death and disability. Chronic inflammation and immune dysregulation are critical in its development. The cardiac immune microenvironment, especially macrophages, drives HF progression, yet its molecular mechanisms and prognostic impact are not fully clear. This study aimed to identify causal immune-related driver genes in the HF inflammatory microenvironment. METHODS: We combined single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) to study how the inflammatory immune microenvironment affects HF risk. Using two public scRNA-seq datasets, we identified differentially expressed genes (DEGs) in HF heart tissues and selected 489 candidate genes. Causal relationships between these genes and HF were tested using expression quantitative trait loci (eQTL) data and HF genome-wide association study (GWAS) summary statistics. RESULTS: MR analysis showed that 65 genes were causally linked to HF risk. These genes were enriched in pathways related to cardiomyopathy, leukocyte migration, natural killer (NK) cell cytotoxicity, neutrophil extracellular traps, and NF-κB signaling. HF hearts displayed increased levels of macrophages, T cells, B cells, lymphoid cells, and mast cells, while neutrophils were reduced. CONCLUSIONS: Our integrated analysis reveals the central role of the cardiac inflammatory immune microenvironment in HF and identifies 65 key genes causally associated with HF susceptibility. These genes influence specific immune pathways and cell infiltration, shaping HF progression, and provide a basis for developing new biomarkers and immune-targeted therapies.

Heart failure (HF)↗
PubMed2024

An insight into the causal relationship between sarcopenia-related traits and venous thromboembolism: A mendelian randomization study.

BACKGROUND: As a geriatric syndrome, sarcopenia has a high prevalence in the old population and represents an impaired state of health with adverse health outcomes. A strong clinical interest in its relationship with venous thromboembolism (VTE), which is a complex trait disease with a heterogeneous annual incidence rate in different countries, has emerged. The relationship between sarcopenia and venous thromboembolism has been reported in observational studies but the causality from sarcopenia to VTE remained unclarified. We aimed to assess the causal effect of sarcopenia on the risk of VTE with the two-sample Mendelian randomization (MR) method. METHODS: Two sets of single-nucleotide polymorphisms (SNPs), derived from two published genome-wide association study (GWAS) meta-analyses and genetically indexing muscle weakness and lean muscle mass separately, were pooled into inverse variance weighted (IVW), weighted median and MR-Egger analyses. RESULTS: No evidence was found for the causal effect of genetically predicted muscle weakness (IVW: OR = 0.90, 95% CI = 0.76-1.06, p = 0.217), whole body lean mass (IVW: OR = 1.01, 95% CI = 0.87-1.17, p = 0.881) and appendicular lean mass (IVW: OR = 1.13, 95% CI = 0.82-1.57, p = 0.445) on the risk of VTE. However, both genetically predicted whole-body lean mass and appendicular lean mass can causally influence diabetes mellitus (IVW of whole-body lean mass: OR = 0.87, 95% CI = 0.78-0.96, p = 0.008; IVW of appendicular lean mass: OR = 0.71, 95% CI = 0.54-0.94, p = 0.014) and hypertension (IVW of whole-body lean mass: OR = 0.92, 95% CI = 0.87-0.98, p = 0.007; IVW of appendicular lean mass: OR = 0.84, 95% CI = 0.73-0.96, p = 0.013). CONCLUSIONS: Genetically predicted sarcopenia does not causally influence VTE directly, but it might still have an indirect effect on VTE incidence via diabetes mellitus and hypertension.

Humans↗
PubMed2026

Identification of NLRP3 and TIPE2 as asthma biomarkers via integrative bioinformatics and Mendelian randomization.

Asthma is a chronic inflammatory airway disease imposing a substantial global health burden. NLRP3 is an immune sensor involved in infection and cellular stress responses. Recent studies suggest that NLRP3 may be involved in the pathogenesis of asthma. We hypothesized that genetic variation in NLRP3 may contribute to asthma susceptibility. However, the causal relationship between NLRP3 and asthma still remains unclear. In this study, bioinformatics analysis using asthma data and R software was performed to identify NLRP3-related genes. We performed weighted gene co-expression network analysis to identify co-expressed genes, resulting in 12 candidate genes. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were used to identify the functions of these candidate genes, revealing their involvement in cellular metabolism. Mendelian randomization analysis of the 12 candidate genes identified 2 biomarkers: NLRP3 and TNFAIP8L2 (TIPE2). We validated their diagnostic value for asthma using the GSE182503 dataset, with area under the curve values of 0.83 and 0.66 for NLRP3 and TIPE2, respectively. This project discusses how NLRP3 promotes asthma pathogenesis, whereas TIPE2 may alleviate it, and explores the potential interplay between them. NLRP3 and TIPE2 may serve as diagnostic biomarkers for asthma: NLRP3 may promote, whereas TIPE2 may alleviate asthma development. Both genes represent potential diagnostic biomarkers and therapeutic targets that warrant further functional investigation.

Asthma↗
PubMed2024

Mendelian randomization study of lipid metabolism characteristics and migraine risk.

BACKGROUND: The association between serum lipids and migraine is controversial. However, randomized controlled trials have suggested that statins may be efficacious for the prevention of migraine. In this study, we aim to investigate the relationship between lipids metabolism and migraine risk. METHODS: Single-nucleotide polymorphisms (SNPs), relating to the serum lipid traits and the effect of lipid-lowering drugs that target APOB, CETP, HMGCR, NPC1L1, and PCSK9, were extracted from genome-wide association studies (GWAS) summary data. The GWAS summary data were obtained from the Global Lipids Genetic Consortium (GLGC), the UK Biobank, and the FinnGen study, respectively. Mendelian randomization (MR) analysis was performed to evaluate the association between serum lipid traits and lipid-lowering drugs with migraine risk. RESULTS: Regarding serum lipids, it was found that SNPs related to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), or triglycerides (TG) levels were not associated with migraine, migraine with aura (MA) or migraine without aura (MO). In addition, genotypes of HMGCR related to higher LDL-C levels were associated with increased risk of migraine (OR = 1.46, p = 0.035) and MA (OR = 2.03, p = 0.008); However, genotypes of PCSK9 related to higher LDL-C levels were associated with decreased risk of migraine (OR = 0.75, p = 0.001) and MA (OR = 0.69, p = 0.004); And genotypes of APOB related to higher LDL-C levels were associated with decreased risk of MO (OR = 0.62, p = 0.000). CONCLUSIONS: There is a relationship between lipid metabolism characteristics and migraine risk. SIGNIFICANCE: Based on the genome-wide association summary data, single-nucleotide polymorphisms (SNPs) related to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), or triglycerides (TG) level were not associated with risk of migraine, migraine with aura (MA) or migraine without aura (MO). However, genotypes of HMGCR related to higher LDL-C levels have shown an increased risk on migraine and MA. And genotypes of APOB or PCSK9 related to higher LDL-C levels have shown a decreased risk on MO, or migraine and MA, respectively. These results suggested that there may be a relationship between lipid metabolism characteristics and the risk for migraine development.

Humans↗
PubMed2023

Causal Associations of Sleep Apnea with Alzheimer's Disease and Cardiovascular Disease: a Bidirectional Mendelian Randomization Analysis.

BACKGROUND: Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer's disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization (MR). METHODS: Using summary statistics from four recent, large genome-wide association studies of SA (n=523,366), AD (n=64,437), CAD (n=1,165,690), and stroke (n=1,308,460), we conducted bidirectional two-sample MR analyses. Our primary analytic method was fixed-effects inverse variance weighted MR; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. RESULTS: We identified a significant causal effect of SA on the risk of CAD (odds ratio (OR IVW ) =1.35 per log-odds increase in SA liability, 95% confidence interval (CI) =1.25-1.47) and stroke (OR IVW =1.13, 95% CI =1.01-1.25). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (BMI) (OR IVW =1.26, 95% CI =1.15-1.39 for CAD risk; OR IVW =1.08, 95% CI =0.96-1.22 for stroke risk). SA was not causally associated with a higher risk of AD (OR IVW =1.14, 95% CI =0.91-1.43). We did not find causal effects of AD, CAD, or stroke on risk of SA. CONCLUSIONS: These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by BMI. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

Preprint↗
PubMed2005

Meta-analysis of genetic studies using Mendelian randomization--a multivariate approach.

In traditional epidemiological studies the association between phenotype (risk factor) and disease is often biased by confounding and reverse causation. As a person's genotype is assigned by a seemingly random process, genes are potentially useful instrumental variables for adjusting for such bias. This type of adjustment combines information on the genotype-disease association and the genotype-phenotype association to estimate the phenotype-disease association and has become known as Mendelian randomization. The information on genotype-disease and genotype-phenotype may well come from a meta-analysis. In such a synthesis, a multivariate approach needs to be used whenever some studies provide evidence on both the genotype-phenotype and genotype-disease associations. This paper presents two multivariate meta-analytical models, which differ in their treatment of the heterogeneities (between-study variances). Heterogeneities on the genotype-phenotype and genotype-disease associations may be highly correlated, but a multivariate model that parameterizes the heterogeneity directly is difficult to fit because that correlation is poorly estimated. We advocate an alternative model that treats the heterogeneities on genotype-phenotype and phenotype-disease as being independent. This model fits readily and implicitly defines the correlation between the heterogeneities on genotype-phenotype and genotype-disease. We show how either maximum likelihood or a Bayesian approach with vague prior distributions can be used to fit the alternative model.

Coronary Disease↗
PubMed2024

Effect of inflammatory cytokines and plasma metabolome on OSA: a bidirectional two- sample Mendelian randomization study and mediation analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder. Inflammatory factors and plasma metabolites are important in assessing its progression. However, the causal relationship between them and OSA remains unclear, hampering early clinical diagnosis and treatment decisions. METHODS: We conducted a large-scale study using data from the FinnGen database, with 43,901 cases and 366,484 controls for our discovery MR analysis. We employed 91 plasma proteins from 11 cohorts (totaling 14,824 participants of European descent) as instrumental variables (IVs). Additionally, we conducted a GWAS involving 13,818 cases and 463,035 controls to replicate the MR analysis. We primarily used the IVW method, supplemented by MR Egger, weighted median, simple mode, and weighted mode methods. Meta-analysis was used to synthesize MR findings, followed by tests for heterogeneity, pleiotropy, and sensitivity analysis (LOO). Reverse MR analysis was also performed to explore causal relationships. RESULTS: The meta-analysis showed a correlation between elevated Eotaxin levels and an increased risk of OSA (OR=1.050, 95% CI: 1.008-1.096; p < 0.05). Furthermore, we found that the increased risk of OSA could be attributed to reduced levels of X-11849 and X-24978 (decreases of 7.1% and 8.4%, respectively). Sensitivity analysis results supported the reliability of these findings. CONCLUSIONS: In this study, we uncovered a novel biomarker and identified two previously unknown metabolites strongly linked to OSA. These findings underscore the potential significance of inflammatory factors and metabolites in the genetic underpinnings of OSA development and prognosis.

Female↗
PubMed2025

Education, socioeconomic status, leisure sedentary behaviors and female infertility: mendelian randomization study.

BACKGROUND: Previous studies have indicated that education, socioeconomic status, and leisure sedentary behavior may be associated with female infertility. However, it remains unclear whether these associations imply causal relationships. METHODS: Genetic variants from genome-wide association studies (GWAS) of education, socioeconomic status, and leisure sedentary behaviors were obtained from the UK Biobank and MRC-IEU database (Medical Research Council Integrative Epidemiology Unit), female infertility data was acquired from the FinnGen Biobank. Univariable and multivariable MR analyses were performed to explore the relationships between these traits and female infertility. RESULTS: The results of the univariate MR analysis indicated that age of full-time education had a protective effect on female infertility (odds ratio [OR] 0.471; 95% confidence interval [CI] 0.24 to 0.93; p&#x2009;=&#x2009;0.03). Multivariable MR and reverse MR studies support the existence of a relationship between them. However, no causal correlation was found between other traits and female infertility. No significant heterogeneity or horizontal pleiotropy was detected, and the stability of the results was confirmed through sensitivity analysis and the leave-one-out test. CONCLUSIONS: A later age of completion of full-time education may be causally related to a reduced risk of female infertility, but no causality is established between other educational levels factors, socioeconomic status, or sedentary behaviors and infertility risk.

Humans↗
PubMed2024

The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study.

BACKGROUND: Previous cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework. METHODS: A total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods. RESULTS: Genetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all p<0.05 while &#x2265;0.00167). The positive causal relationship between depression, years of education and FD was still significant in multivariate MR analyses. CONCLUSIONS: Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.

Humans↗
PubMed2026

Uncovering metabolite-immune interactions in the pathogenesis of psoriatic arthritis: A 2-sample Mendelian randomization study.

PsA is a chronic inflammatory joint condition associated with psoriasis, and its underlying mechanisms are not fully elucidated. Serum metabolites, as direct reflections of metabolic status, may influence disease progression by regulating immune cell function; however, the causal relationships and specific pathways require further investigation. The present investigation utilized a 2-sample bidirectional MR methodology, leveraging extensive pooled GWAS data to thoroughly evaluate the causal relationships between 1440 serum metabolites and PsA. Additionally, mediation MR analysis was performed to explore the possible mediating effects of 731 immune cell characteristics. In the primary analysis, inverse-variance weighted was employed, and this was further supported by various sensitivity analyses to confirm the reliability of the findings. The genetic method to infer causality analysis revealed significant positive causal associations between 10 serum metabolites and PsA risk, with quinolinate levels demonstrating the most significant correlation (OR&#x2005;=&#x2005;1.56, 95% CI: 1.26-1.93); while 4 metabolites (e.g., citrate levels, OR&#x2005;=&#x2005;0.74, 95% CI: 0.61-0.89) exhibited protective effects. Regarding immune cells, 6 cellular features (e.g., CD20 on B cells) were positively correlated with disease risk, whereas 5 features (primarily HLA-DR expression on monocyte subsets) showed negative correlations. Mediation analysis identified 3 significant pathways,the percentage of the effect explained by the mediator: N6,N6,N6-trimethyllysine levels mediated via B cells (CD20 on IgD+ CD38br), with a proportion of 33.2%; 1-stearoyl-2-docosahexaenoyl-GPE (18:0/22:6) levels mediated through monocytes (HLA-DR on CD14- CD16-) with a 32.0% proportion; the unknown metabolite X-24736 also mediated 42.1% of the protective effect via the same monocyte phenotype. This study revealed that elevated amino acid-related metabolites and glycerophospholipids significantly increase PsA risk through immune cell effects. These are closely associated with PsA pathogenesis and may serve as potential biomarkers. The novel findings underscore metabolic-immune interactions as targets for biomarkers and therapies in PsA, advancing personalized medicine.

Humans↗
PubMed2006

Insight into the nature of the CRP-coronary event association using Mendelian randomization.

BACKGROUND: It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded. METHODS: We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies). RESULTS: CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs. CONCLUSIONS: A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.

C-Reactive Protein↗