Genetic Instrumental Variables Research Articles

Appraising the causal effects of circulating micronutrients on liver cirrhosis: Evidence from large‐scale Mendelian randomization analysis

AbstractAimsObservational research has identified links between micronutrient levels and chronic liver disease. However, the lack of randomized controlled experiments has impeded the ability to establish a cause‐and‐effect connection regarding micronutrients and cirrhosis of the liver. This Mendelian randomization (MR) analysis aimed to examine the causal impact of micronutrients on liver cirrhosis.MethodsWe selected genetic instrumental variables related to 12 micronutrients from genome‐wide studies on individuals of European descent, covering an array of over 9,851,867 single nucleotide polymorphisms and 460,351 participants. Data from patients with cirrhosis in the FinnGen database (https://www.finngen.fi/fi) were used. A two‐sample MR approach was employed to establish genetically causal estimates. Primary analyses used random effects and inverse variance weighted (IVW) methods, with additional sensitivity analyses for validation. MR–Egger intercept analysis and Cochran's Q test assessed horizontal pleiotropy and heterogeneity. Furthermore, multivariable Mendelian randomization (MVMR) was conducted to address potential confounding variables.ResultsIVW and weighted median methods showed that most micronutrients included were not significantly associated with a genetic susceptibility to liver cirrhosis. However, MR analysis demonstrated a significant association between circulating vitamin D levels and a reduced risk of liver cirrhosis (odds ratio IVW = 0.53, p < 0.010). The MR–Egger intercept showed no evidence of horizontal pleiotropy (p = 0.178), whereas Cochran's Q test found no heterogeneity (p = 0.799). Furthermore, MVMR analysis confirmed vitamin D was identified as a factor that independently mitigates the risk of liver cirrhosis.ConclusionThis research constitutes the most comprehensive MR investigation in this field, providing evidence supporting a protective link between circulating vitamin D levels and cirrhosis incidence. It suggests that maintaining sufficient vitamin D could be a cost‐effective strategy for early intervention in liver cirrhosis.

Causal Associations Between Tea Consumption and REM Sleep Behavior Disorder: A Mendelian Randomization Study.

Previous studies have shown that tea consumption may have a protective effect against neurodegenerative diseases. However, the exact causal relationship between tea consumption and the precursor stages of certain neurodegenerative diseases, namely REM sleep behavior disorder (RBD), remains unclear. To evaluate the causal association between tea consumption and RBD, we employed a Mendelian randomization study. We identified genetic instrumental variables that are significantly associated with tea consumption through genome-wide association studies (GWAS) in European populations. Bidirectional two-sample Mendelian randomization was utilized to determine the causal relationship between tea consumption and RBD, while sensitivity analyses were further employed to evaluate the robustness of the results. The multivariate Mendelian randomization method was used to assess the influence of relevant confounding factors on the results. In the MR analysis using the inverse variance weighting method, a significant causal relationship between tea consumption and RBD was observed (OR=0.046, 95% CI 0.004-0.563, p=0.016). The consistency of findings across maximum likelihood, MR PRESSO, and multivariate MR after adjusting for potential confounding further supports this causal association. Sensitivity analyses revealed no evidence of heterogeneity or pleiotropy. The findings of our study demonstrate a robust causal association between tea consumption and RBD, indicating that tea consumption may serve as a protective factor against the development of RBD.

Association of hidradenitis suppurativa (HS) with waist circumference: A bidirectional two-sample Mendelian randomization study of HS with metabolic syndrome.

Observational studies have suggested an associations between hidradenitis suppurativa (HS) and metabolic syndrome (MetS) and its components. However, it remains unclear whether the relationship is causal or not. Our study aimed to investigate the causal association of HS with MetS and its components. We performed a bidirectional, two-sample Mendelian randomization study using summary-level data from the most comprehensive genome-wide association studies of HS (n = 362 071), MetS (n = 291 107), waist circumference (n = 462 166), hypertension (n = 463 010) fasting blood glucose (FBG, n = 200 622), triglycerides (n = 441 016), and high-density lipoprotein cholesterol (HDL-C, n = 403 943). Genetic instrumental variables were constructed by identifying single nucleotide polymorphisms associated with the corresponding factors. The random-effects inverse-variance weighted method was applied as the primary method. The results showed that genetically predicted HS was positively associated with waist circumference risk in both directions. High waist circumference increased the risk of HS (odds ratio [OR] 4.147; 95% confidence interval [CI] 2.610-6.590; p = 1.746 × 10-9). In addition, HS was also affected by waist circumference (OR 1.009; 95% CI 1.006-1.012; p = 3.08 × 10-7). No causal relationships were found between HS and MetS or its components other than waist circumference. The findings highlight the importance of early intervention for obesity in HS patients. Further studies are needed to determine the pathophysiology of HS associated with MetS and its components.

Association and causal impact of TERT genetic variants on peripheral blood leukocyte telomere length and cerebral small vessel disease risk in a Chinese Han population: a mendelian randomization analysis

BackgroundPrevious observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD.MethodsFive TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk.ResultsModel association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk.ConclusionMultiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.

Mendelian randomization of plasma lipidome, inflammatory proteome and heart failure.

Heart failure (HF) is a global health issue, with lipid metabolism and inflammation critically implicated in its progression. This study harnesses cutting-edge, expanded genetic information for lipid and inflammatory protein profiles, employing Mendelian randomization (MR) to uncover genetic risk factors for HF. We assessed genetic susceptibility to HF across 179 lipidomes and 91 inflammatory proteins using instrumental variables (IVs) from recent genome-wide association studies (GWASs) and proteome-wide quantitative trait loci (pQTL) studies. GWASs involving 47309 HF cases and 930014 controls were obtained from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium. Data on 179 lipids from 7174 individuals in a Finnish cohort and 91 inflammatory proteins from a European pQTL study involving 14824 individuals are available in the HGRI-EBI catalogue. A two-sample MR approach evaluated the associations, and a two-step mediation analysis explored the mediation role of inflammatory proteins in the lipid-HF pathway. Sensitivity analyses, including MR-RAPS (robust adjusted profile score) and MR-Egger, ensured result robustness. Genetic IVs for 162 lipids and 74 inflammatory proteins were successfully identified. MR analysis revealed a genetic association between HF and 31 lipids. Among them, 18 lipids, including sterol ester (27:1/18:0), cholesterol, 9 phosphatidylcholines, phosphatidylinositol (16:0_20:4) and 6 triacylglycerols, were identified as HF risk factors [odds ratio (OR)=1.037-1.368]. Cholesterol exhibited the most significant association with elevated HF risk [OR=1.368, 95% confidence interval (CI)=1.044-1.794, P=0.023]. In the inflammatory proteome, leukaemia inhibitory factor receptor (OR=0.841, 95% CI=0.789-0.897, P=1.08E-07), fibroblast growth factor 19 (OR=0.905, 95% CI=0.830-0.988, P=0.025) and urokinase-type plasminogen activator (OR=0.938, 95% CI=0.886-0.994, P=0.030) were causally negatively correlated with HF, whereas interleukin-20 receptor subunit alpha (OR=1.333, 95% CI=1.094-1.625, P=0.004) was causally positively correlated with HF. Mediation analysis revealed leukaemia inhibitory factor receptor (mediation proportion: 23.5%-25.2%) and urokinase-type plasminogen activator (mediation proportion: 9.5%-10.7%) as intermediaries in the lipid-inflammation-HF pathway. No evidence of directional horizontal pleiotropy was observed (P>0.05). This study identifies a genetic connection between certain lipids, particularly cholesterol, and HF, highlighting inflammatory proteins that influence HF risk and mediate this relationship, suggesting new therapeutic targets and insights into genetic drivers in HF.

Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension

BackgroundPrevious research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS).MethodsTotal of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH.ResultsOur analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054–1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064–1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, β = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, β = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines.ConclusionOur analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

Causal association of micronutrients and supplements with pressure ulcer: A Mendelian randomization study.

Pressure ulcer (PU) is known to be associated with abnormalities of micronutrient status. However, to date, it is not clear whether a causal relationship exists between circulating levels of micronutrients and their supplementations and PU. A two-sample Mendelian randomization (MR) study was conducted using summary statistics from Genome-Wide Association Studies (GWAS). Genetic instrumental variables (IVs) for 13 micronutrients were identified from a GWAS of 67582 participants, IVs for supplement zinc were acquired from 18826 cases and 44255880 controls, and IVs for PU were obtained from 663 PUs and 207482 controls. The MR analysis was conducted using the MR base platform. The main analysis method was inverse variance weighted (IVW) analysis, supplemented by MR Egger, Weighted median, Weighted mode, and Simple mode analyses. Heterogeneity was assessed using Cochran's Q statistic for MR-IVW and Rucker's Q statistic for MR-Egger. Pleiotropy was determined bythe MR-Eggerregression. Sensitivityanalysiswasconductedusingthe leave-one-outmethod, and publication bias was evaluated using funnel plots. Genetically predicted lower circulating zinc levels were found to be causally linked to the development of PU (OR=0.758, 95%CI 0.583-0.987, P=0.040). However, there was no significant evidence of a causal relationship between supplemental zinc intake and PU development (P>0.05). Additionally, no causal association was observed between the other circulating micronutrients and the occurrence of PU. Furthermore, there was no indication of horizontal pleiotropy or heterogeneity among genetic variants (P>0.05), and the robustness of the findings was confirmed through leave-one-out tests and funnel plots. Our findings indicate a potential causal association between circulating zinc levels and decreased risk of PU. However, zinc supplementation did not demonstrate a significant reduction in the risk of PU. Further research is warranted to elucidate the underlying mechanisms through which zinc influences the pathogenesis of PU and evaluate the efficacy of zinc supplementation in the prevention and management of PU.

The integrity of the corticospinal tract and corpus callosum, and the risk of ALS: univariable and multivariable Mendelian randomization

Studies suggest that amyotrophic lateral sclerosis (ALS) compromises the integrity of white matter fiber tracts, primarily affecting motor fibers. However, it remains uncertain whether the integrity of these fibers influences the risk of ALS. We performed bidirectional two-sample Mendelian randomization (MR) and multivariable MR analyses to evaluate the associative relationships between the integrity of fiber tracts [including the corticospinal tract (CST) and corpus callosum (CC)] and the risk of ALS. Genetic instrumental variables for specific fiber tracts were obtained from published genome-wide association studies (GWASs), including 33,292 European individuals from five diffusion magnetic resonance imaging (dMRI) datasets. Summary-level GWAS data for ALS were derived from 27,205 ALS patients and 110,881 controls. The MR results suggested that an increase in the first principal component (PC1) of fractional anisotropy (FA) in the genu of the CC (GCC) was correlated with an increased risk of ALS (PFDR = 0.001, odds ratio = 1.363, 95% confidence interval 1.178–1.577). Although other neuroimaging phenotypes [mean diffusivity in the CST, radial diffusivity (RD) in the CST, FA in the GCC, PC1 in the body of the CC (BCC), PC1 in the CST, and RD in the GCC] did not pass correction, they were also considered to have suggestive associations with the risk of ALS. No evidence revealed that ALS caused changes in the integrity of fiber tracts. In summary, the results of this study provide genetic support for the potential association between the integrity of specific fiber tracts and the risk of ALS. Greater fiber integrity in the GCC and BCC may be a risk factor for ALS, while greater fiber integrity in the CST may have a protective effect on ALS. This study provides insights into ALS development.

Causal relationship between Alzheimer's disease and unstable angina: a bidirectional Mendelian randomization analysis.

Research from observational studies has demonstrated a link between Alzheimer's disease (AD) and a higher risk of cardiovascular disease (CVD). Uncertainty surrounds the exact genetic cause of AD and coronary heart disease, particularly unstable angina (UA). Mendelian randomization (MR) analysis was used to examine the causal genetic link between AD and UA to evaluate the impact of AD on UA. The purpose of the bidirectional MR analysis was to investigate the link between exposure and illness causation. Genetic instrumental variables for AD were obtained from European populations using genome-wide association studies (GWAS). The primary causal conclusions were obtained using the inverse variance weighted approach (IVW), and other sensitivity analysis techniques were employed. Sensitivity analyses were carried out to evaluate heterogeneity and horizontal pleiotropy to guarantee accurate MR results. An elevated risk of UA was linked to genetically predicted AD (IVW: OR=3.439, 95% CI: 1.565-7.555, P=0.002). A substantial genetic relationship between UA and the risk of AD was not supported by any evidence in the reverse study (IVW: OR=0.998, 95% CI: 0.995-1.001, P=0.190). Various MR techniques produced consistent results. Sensitivity analysis revealed no discernible heterogeneity or horizontal pleiotropy. One risk factor for UA that we found in our bidirectional Mendelian randomization trial was AD. This highlights the necessity of researching the underlying molecular mechanisms linked to AD and UA as well as the possibility of creating individualized treatment plans based on genetic data.

No evidence for causal effects of C-reactive protein (CRP) on chronic pain conditions: a Mendelian randomization study.

We conducted a Mendelian randomization (MR) study to examine causal associations of C-reactive protein (CRP) with (1) spinal pain; (2) extent of multisite chronic pain; and (3) chronic widespread musculoskeletal pain. Two-sample MR study. We used summary statistics from publicly available genome-wide association studies (GWAS) conducted in multiple cohorts and biobanks. Genetic instrumental variables were taken from an exposure GWAS of CRP (n=204,402). Outcome GWASs examined spinal pain (n=1,028,947), extent of multisite chronic pain defined as the number of locations with chronic pain (n=387,649), and chronic widespread pain (n=249,843). We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis and sensitivity analyses using other methods. We calculated odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values, using a Bonferroni correction (p<0.0166) to account for 3 primary comparisons. Greater serum CRP (mg/L) was not significantly causally associated with spinal pain (OR=1.04, 95% CI 1.00-1.08; p=0.07) in IVW analysis. Greater serum CRP also showed no significant causal association with extent of multisite chronic pain in IVW analysis (beta coefficient= 0.014, standard error=0.011; p=0.19). CRP also showed no significant causal association with chronic widespread pain in IVW analysis (OR=1.00, 95% CI 1.00-1.00; p=0.75). All secondary and sensitivity analyses also showed no significant associations. This MR study found no causal association of CRP on spinal pain, the extent of chronic pain, or chronic widespread pain. Future studies examining mechanistic biomarkers for pain conditions should consider other candidates besides CRP.

Mendelian randomization analysis of psoriasis and psoriatic arthritis associated with risks of ulcerative colitis.

This study is designed to explore the potential causal relationship between psoriasis and psoriatic arthritis (PsA) while investigating the genetic basis shared by these inflammatory diseases. Significant single nucleotide polymorphisms (SNPs) associated with UC, psoriasis, and PsA were selected as genetic instrumental variables using Genome-Wide Association Study (GWAS) datasets. Additionally, Mendelian randomization (MR) methods, including inverse-variance weighting (IVW), MR-Egger regression, and Weighted Median (WME), were utilized to evaluate the causal relationships between these diseases. Moreover, sensitivity analysis and heterogeneity testing were conducted to validate the stability of the results. A total of 123 significant SNPs associated with psoriasis, PsA, and UC were identified as genetic instrumental variables based on GWAS datasets. The analysis revealed a 36% increased risk of UC with psoriasis (odds ratio [OR]=1.350, 95% confidence interval [CI]=1.065-1.729, P=0.012) and a 32.9% increased risk of UC with PsA (OR=1.329, 95% CI=1.176-1.592, P<0.001). Further analysis showed a 43.5% increased risk of psoriasis with UC (OR=1.435, 95% CI=1.274-1.831, P<0.001) and a 45.8% increased risk of PsA with UC (OR=1.458, 95% CI=1.166-1.822, P=0.0013). In addition, sensitivity analysis and heterogeneity testing demonstrated the high stability of these results. Particularly, neither MR-Egger regression analysis nor leave-one-out analysis revealed significant heterogeneity or pleiotropy bias, indicating the reliability of these causal estimates. Moreover, the use of the MR-PRESSO further confirmed the positive correlation between psoriasis and UC, and the corrected estimates remained consistent with IVW analysis results after excluding potential outlier SNPs, enhancing the credibility of the analysis. This study strengthens the understanding of the genetic and causal relationships among UC, psoriasis, and PsA through GWAS and MR methods, revealing the genetic basis they may share. These findings not only provide a novel perspective on the comorbidity mechanisms of these diseases but also offer a valuable reference for the development of future treatment strategies and intervention measures.

The interplay between systemic inflammatory factors and endometriosis: A bidirectional mendelian randomization study

ObjectiveTo utilize vast genetic data to reveal the interplay between 41 systemic inflammatory factors and endometriosis. DesignBidirectional Mendelian randomization study. Mains outcome measuresThis study obtained believable genetic instrumental variables for systemic inflammatory factors. The effect of systemic inflammatory factors on different endometriosis phenotypes, and the effect of endometriosis on the concentrations of systemic inflammatory factors were investigated. ResultsIn this mendelian randomization study, we found 20 causal relationships involving 18 systemic inflammatory factors and it was shown that Monocyte chemotactic protein-1, Macrophage inflammatory protein-1a, Granulocyte colony-stimulating factor, Macrophage migration inhibitory factor, Interleukin-4, Interleukin-5, Interleukin-8, Interleukin-9, Interleukin-12p70, Interleukin-16, and Interleukin-17 may be the upstream causes of endometriosis (P<0.05). Additionally, if the definition of exposure in the mendelian randomization was endometriosis, it could suggestively cause an increase in Eotaxin, cutaneous T-cell attracting chemokine, and Interferon gamma-induced protein 10 levels, and a decrease in growth-regulated oncogene-alpha, Interleukin-2 receptor, alpha subunit, platelet-derived growth factor BB, and Interleukin-18 (P<0.05). Reverse causality was not observed between a single systemic inflammatory factor and endometriosis. ConclusionsOur findings indicate that several systemic inflammatory factors may act as the initiator at the onset of endometriosis. Additionally, several other inflammatory factors are far more probable to involved downstream during disease development.

Causal association between immune cells and lung cancer risk: a two-sample bidirectional Mendelian randomization analysis.

Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored. We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations. Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (P<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (ORIVW =0.885; 95% CI: 0.798-0.983; P IVW =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (ORIVW =1.054; 95% CI: 1.010-1.100; P IVW =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (ORIVW =0.941; 95% CI: 0.898-0.987; P IVW =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) as well as on plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) in lung squamous cell carcinoma. This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.

Causal association of circulating cytokines with the risk of lung cancer: a Mendelian randomization study.

Lung cancer is the deadliest and most prevalent malignancy worldwide. While smoking is an established cause, evidence to identify other causal factors remains lacking. Current research indicates chronic inflammation is involved in tumorigenesis and cancer development, though the specific mechanisms underlying the role of inflammatory cytokines in lung cancer pathogenesis remain unclear. This study implemented Mendelian randomization (MR) analysis to investigate the causal effects of circulating cytokines on lung cancer development. We performed a two-sample MR analysis in Europeans utilizing publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms significantly associated with cytokine were selected as genetic instrumental variables. Genetically predicted levels of the chemokine interleukin-18 (IL-18) (OR = 0.942, 95% CI: 0.897-0.990, P = 0.018) exerted significant negative causal effects on overall lung cancer risk in this analysis. Examining specific histologic subtypes revealed further evidence of genetic associations. Stem cell factor (SCF) (OR = 1.150, 95% CI: 1.021-1.296, P = 0.021) and interleukin-1beta (IL-1β) (OR = 1.152, 95% CI: 1.003-1.325, P = 0.046) were positively associated with lung adenocarcinoma risk, though no inflammatory factors showed causal links to squamous cell lung cancer risk. Stratified by smoking status, interferon gamma-induced protein 10 (IP-10) (OR = 0.861, 95% CI: 0.781-0.950, P = 0.003) was inversely associated while IL-1β (OR = 1.190, 95% CI: 1.023-1.384, P = 0.024) was positively associated with lung cancer risk in ever smokers. Among never smokers, a positive association was observed between lung cancer risk and SCF (OR = 1.474, 95% CI: 1.105-1.964, P = 0.008). Importantly, these causal inferences remained robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode and simple mode regressions. Sensitivity analyses also excluded potential bias stemming from pleiotropy. This MR study found preliminary evidence that genetically predicted levels of four inflammatory cytokines-SCF, IL-1β, IL-18, and IP-10-may causally influence lung cancer risk in an overall and subtype-specific manner, as well as stratified by smoking status. Identifying these cytokine pathways that may promote lung carcinogenesis represents potential new targets for the prevention, early detection, and treatment of this deadly malignancy.

Causal Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.

There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer's disease (AD). However, it is unclear whether the two are causally related. To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis. Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR-Egger regression, weighted median, simple mode, and weighted mode were applied to assess the pathogenic associations between the two diseases, and sensitivity analyses were used to further validate the robustness of the results. The results of forward MR analysis with T2DM as the exposure were [OR = 0.998, 95% CI (0.975∼1.021), p = 0.857], and the results of reverse MR analysis with AD as the exposure were [OR = 0.966, 95% CI (0.934∼0.999), p = 0.043]. The results showed no significant association between T2DM and AD at the gene level (p < 0.025). Sensitivity analyses were consistent with the results of the main analysis, confirming the robustness of the study. T2DM and AD may not be genetically causally associated.

Genetic evidence for a causal link between gut microbiota and arterial embolism and thrombosis: a two-sample Mendelian randomization study.

Previous research has hinted at a crucial link between gut microbiota and arterial embolism and thrombosis, yet the causal relationship remains enigmatic. To gain a deeper understanding, we aimed to comprehensively explore the causal relationship and elucidate the impact of the gut microbiota on the risk through a two-sample Mendelian randomization (MR) study. Genetic instrumental variables for gut microbiota were identified from a genome-wide association study (GWAS) of 18,340 participants. Summary statistics for IBS were drawn from a GWAS including 1,076 cases and 381,997 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the weighted median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. We identified three bacterial traits that were associated with the risk of arterial embolism and thrombosis: odds ratio (OR): 1.58, 95% confidence interval (CI): 1.08-2.31, p = 0.017 for genus Catenibacterium; OR: 0.64, 95% CI: 0.42-0.96, p = 0.031 for genus Dialister; and OR: 2.08, 95% CI: 1.25-3.47, p = 0.005 for genus Odoribacter. The results of sensitivity analyses for these bacterial traits were consistent (P<0.05). Our systematic analyses provided evidence to support a potential causal relationship between several gut microbiota taxa and the risk of arterial embolism and thrombosis. More studies are required to show how the gut microbiota affects the development of arterial embolism and thrombosis.

No causal link between herpes zoster and ischemic stroke: evidence from Mendelian randomization study

ABSTRACT Objective The association between herpes zoster (HZ) and stroke has been the subject of much previous research. Nevertheless, the connection remains ambiguous. A two-sample Mendelian randomisation study was conducted to explore the potential causal link between HZ and ischaemic stroke, including its subtypes. Methods For our MR analysis, we identified genetic instrumental variables related to both HZ and stroke by screening two prominent publicly accessible genome-wide association study databases. The primary approach involved using the inverse variance weighting method. To supplement this, we also employed methods such as MR-Egger regression, the weighted median approach, simple and weighted models. Lastly, to ascertain the stability and reliability of the results, we conducted tests for heterogeneity detection, horizontal pleiotropy assessment, and a leave-one-out analysis; Results The genetically predicted HZ did not indicate an association with stroke risk ([OR] 1.041; 95% [CI] 0.958–1.131;p = 0.336). This lack of association also held true for different subtypes of stroke: ischaemic stroke (OR = 1.047, 95% CI = 0.955–1.148, p = 0.323), large vessel stroke (OR = 1.13, 95% CI = 0.90–1.41, p = 0.272), cardioembolic stroke (OR = 1.020, 95% CI = 0.859–1.211, p = 0.816), small vessel stroke (OR = 1.14, 95% CI = 0.93–1.40, p = 0.195), and lacunar stroke (OR = 1.195, 95% CI = 0.967–1.476, p = 0.097). Conclusion This MR study showed that not uncover a causal link between herpes zoster and ischaemic stroke. Additional research will be necessary in the future to shed light on the fundamental mechanisms involved.

Liposomes have a direct effect on multiple myeloma: a Mendelian randomization study.

Multiple myeloma (MM), a malignant disease of plasma cells originating in the bone marrow, is influenced significantly by genetic factors. Although plasma liposomes have been linked to MM, the nature of their potential causal relationship remains to be elucidated. This study aims to explore this relationship using Mendelian randomization (MR) analysis. Liposome-associated genetic instrumental variables (IVs) were identified from plasma lipidomics data of 7,174 Finnish individuals within a Genome-Wide Association Study (GWAS) pooled database. A MM pooled dataset was sourced from a GWAS meta-analysis encompassing 150,797 individuals, including 598 MM patients and 218,194 controls. These IVs underwent MR analysis, adhering to strict criteria for correlation, independence, and the exclusion of confounders. The inverse variance weighted (IVW) method, MR-Egger method, weighted median (WM) method, and simple median were utilized for MR analysis assessment, alongside Cochran's Q test, MR-Egger intercept, MR-Pleiotropy Residual Sum and Outlier (MR-RESSO) method, and leave-one-out analysis for evaluating heterogeneity, multiplicity, and instrumental bias. The study identified 88 significant, independent single nucleotide polymorphisms (SNPs) as IVs for MR analysis, each with an F-statistic value above 10, indicating robustness against weak instrument bias. IVW analysis revealed associations between six plasma liposome components and MM risk (p < 0.05). Phosphatidylinositol (16:0_18:1) serum levels (odds ratio [OR] = 1.769, 95% confidence interval [CI]: 1.132-2.763, p = 0.012) and triacylglycerol (56:4) levels (p = 0.026, OR = 1.417, 95% CI: 1.042-1.926) were positively correlated with the risk of multiple myeloma development. Phosphatidylethanolamine (18:0_20:4) (p = 0.004, 95% CI: 0.621-0.916, OR = 0.754), phosphatidylcholine (18:2_20:4) (p = 0.004, OR = 0.680, 95% CI: 0.519-0.889), sterol ester (27:1/18:3) levels (p = 0.013, OR = 0.677, 95% CI: 0.498-0.922), and phosphatidylcholine (O-18:2_20:4) levels (OR = 0.710, 95% CI: 0.517-0.913, p = 0.033) were negatively associated with the risk of developing multiple myeloma. The Cochran's Q test did not detect statistical method heterogeneity, nor did the MR-RESSO test or the MR-Egger intercept detect horizontal pleiotropy; leave-one-out analyses confirmed the absence of bias from individual SNPs. Our findings suggest a complex relationship between plasma liposome components and MM risk. Elevated serum levels of triacylglycerol and phosphatidylinositol are positively associated with MM risk, while certain phospholipids and sterol esters offer a protective effect. This study provides valuable insights into the clinical relevance of liposomes in the pathology of multiple myeloma.

Genetic causal relationship between multiple immune cell phenotypes and Parkinson's disease: a two-sample bidirectional Mendelian randomization study.

The exact etiology of Parkinson's disease (PD), a degenerative disease of the central nervous system, is unclear. It is currently believed that its main pathological basis is a decrease in dopamine concentration in the striatum of the brain. Although many researchers have previously focused on the critical role of the immune response in PD, there has been a lack of valid genetic evidence for a causal association between specific immune cell traits and phenotypes and PD. We employed Mendelian randomization (MR) as an analytical method to effectively assess genetic associations between exposure and outcome. Based on the largest Genome-Wide Association Study (GWAS) dataset to date, causal associations between multiple immune cell phenotypes and PD were validly assessed, controlling for confounding factors by using single-nucleotide polymorphisms (SNPs), which are genetic instrumental variables that are randomly assigned and not subject to any causality. By testing 731 immune cell phenotypes and their association with PD, the results of inverse variance weighting (IVW) analysis suggested that after Bonferroni correction multiple immune cell phenotypes had no statistically significant effect on PD. It is worth mentioning that some phenotypes with unadjusted P values (P < 0.05), including 40 immune phenotypes, that were located on the cDC panel, the Treg panel, the Maturation stages of T cell panel, the TBNK panel, the B cell panel, the Myeloid cell panel, and the Monocyte panel were considered to have nominal associations with PD. In addition, PD could have an effect on certain immunophenotypes located on the Myeloid cell panel and the Monocyte panel; the specific immunophenotypic results and statistical analysis values are shown in the text. The results of sensitivity analyses suggested that none of these observed the presence of horizontal pleiotropy. Our study identified a close link between immune cells and PD, and the results of this study provide ideas for the study of the immune mechanism of PD and the exploration of effective therapeutic means.NEW & NOTEWORTHY In this study, based on the GWAS Immunophenotyping Database, a Mendelian randomization approach was used to assess the genetic causal associations between 731 immunophenotypes and traits and Parkinson's disease (PD), which not only provides a reference for the immune response mechanism of PD but also provides ideas for exploring the effective diagnosis and treatment of PD.

Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure

Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed a GWAS of HF to identify genetic instrumental variables (GIVs) for HF and to enable bidirectional Mendelian randomization (MR) analysis between T2D and HF. We identified 61 genomic loci, significantly associated with all-cause HF in 114,275 individuals with HF and over 1.5 million controls of European ancestry. Using a two-sample bidirectional MR approach with 59 and 82 GIVs for HF and T2D, respectively, we estimated that T2D increased HF risk (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to the study design of index cases. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program and replicated the associations in the UK Biobank. Our MR findings provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci.