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PubMed2025

Causal relationship between frailty and diabetes subtypes: A bidirectional Mendelian randomization study.

Frailty and diabetes mellitus (DM) are closely linked, but their causal relationship remains unclear. This study aims to determine the bidirectional causal relationship between frailty and different DM subtypes using Mendelian randomization (MR). We performed a 2-sample MR analysis using summary statistics from large-scale genome-wide association studies. The inverse-variance weighting method was the primary analytical approach, with MR-Egger regression and weighted median methods for sensitivity analysis. Horizontal pleiotropy and heterogeneity were assessed using MR-PRESSO and Cochran Q test. Genetically predicted frailty was significantly associated with an increased risk of type 2 diabetes (T2DM) and gestational diabetes (GDM) (odds ratio [OR] = 2.142, 95% confidence interval [CI]: 1.751-2.621, P < .001; OR = 2.280, 95% CI: 1.368-3.800, P = .002), but no causal relationship was observed for type 1 diabetes or glycemic traits (P > .05). Conversely, genetically predicted type 1 diabetes, T2DM, GDM, and postprandial glucose levels (2-hour post-load glucose) increased the risk of frailty (OR = 1.026, 95% CI: 1.014-1.038, P < .001; OR = 1.046, 95% CI: 1.033-1.058, P < .001; OR = 1.068, 95% CI: 1.040-1.096, P < .001; OR = 1.095, 95% CI: 1.049-1.144, P < .001). Sensitivity analyses confirmed the robustness of these findings. This study provides genetic evidence supporting a bidirectional causal relationship between frailty and diabetes, particularly T2DM and GDM. These findings highlight the need for early frailty screening in diabetic patients and better metabolic management in frail populations.

Humans↗

PubMed2025

Causal relationship between albumin, total protein, and colorectal cancer risk: A 2-sample Mendelian randomization study.

Albumin (ALB) and total protein (TP) are vital constituents of the blood, and their levels and roles in the risk of colorectal cancer (CRC) are of significance. Previous observational studies have reported correlations among ALB, TP, and CRC. However, the existence of a causal relationship between ALB and CRC in European populations has not been adequately investigated and the causal link between TP and CRC remains unexplored. To address these gaps, we applied Mendelian randomization (MR) to investigate the potential causal relationship between ALB, TP, and CRC. Two-sample MR analysis was used to investigate whether there was a causal relationship between ALB, TP, and CRC. Our exposure data were extracted from genome-wide association study (GWAS) databases sourced from the UK Biobank, containing 315,268 and 314,921 Europeans participants for ALB and TP analyses, respectively. Single nucleotide polymorphisms that were significantly associated with ALB and TP were assessed using GWAS datasets. Our data were derived from the FinnGen Consortium CRC GWAS, which contained 6509 CRC cases and 28,7137 controls. Causal inference between ALB, TP, and CRC was performed using 3 MR methods: inverse variance weighting (IVW), MR-Egger, and weighted median. The IVW analysis showed no significant causal association between ALB and CRC (OR = 1.04, 95% CI = 0.89-1.21, P = .65). In contrast, the IVW analysis for TP and CRC showed a significant causal association (OR = 0.78, 95% CI = 0.66-0.92, P = .003), suggesting a reduced risk of CRC. Through a 2-sample MR study investigating the causal relationship between ALB, TP, and CRC in a European population, our findings revealed a significant causal relationship between TP and a reduced risk of CRC.

Humans↗

PubMed2025

Plasma metabolites mediate the causal relationship between gut microbiota and erectile dysfunction: insights from Mendelian randomization study.

BACKGROUND: While the relationship between gut microbiota and erectile dysfunction (ED) has been reported, the specific pathways involved remain unclear. AIM: This study aims to investigate the causal relationship between gut microbiota and ED, and to identify the potential role of plasma metabolites as mediators. METHODS: Utilizing aggregated genome-wide association study (GWAS) data, a comprehensive two-sample Mendelian randomization (MR) analysis was performed involving 196 gut microbiota taxa, 1400 plasma metabolites and ED. Causal relationships between gut microbiota, plasma metabolites and ED were explored. In addition, mediation analysis was applied to identify the pathway from gut microbiota to ED mediated by plasma metabolites. OUTCOMES: This study reveals that plasma metabolites act as mediators regulating the influence of gut microbiota on ED. RESULTS: MR analysis identified causal relationships between six gut microbial taxa and ED, with Butyrivibrio increasing the risk of ED, while Alistipes, Prevotella 9, Dialister, Marvinbryantia, and LachnospiraceaeUCG010 exhibited protective effects. Additionally, 45 plasma metabolites demonstrated causal associations with ED. Finally, mediation analysis revealed four mediation relationships. Sensitivity analysis indicated no heterogeneity or pleiotropy in this study. CLINICAL IMPLICATIONS: Modulating gut microbiota or targeting specific metabolites may offer new therapeutic approaches for ED, highlighting the potential for microbiome-based interventions. STRENGTHS AND LIMITATIONS: The MR approach and large-scale GWAS data provide robust causal evidence, but the findings are limited by their focus on European populations and lack of experimental validation. Further studies are needed to confirm these mechanisms in diverse cohorts and functional models. CONCLUSION: This study establishes a causal link between gut microbiota, plasma metabolites, and ED, identifying specific microbial taxa and metabolites as key contributors to ED risk. The mediating role of plasma metabolites highlights potential therapeutic strategies, such as probiotics or dietary interventions targeting harmful metabolites.

Mendelian randomization↗

PubMed2025

Causal relationship between white matter structural connectivity and epilepsy.

White matter structural connectivity has recently been linked to epilepsy pathogenesis, yet its causal role remains unclear. This study used Mendelian randomization (MR) to investigate the causal relationship between white matter structural connectivity and epilepsy. GWAS summary statistics for white matter structural connectivity were sourced from the UK Biobank, while epilepsy data were obtained from FinnGen R10 and the International League Against Epilepsy (ILAE). Our MR analysis revealed significant causal links between white matter structural connectivity and epilepsy risk. Increased connectivity between the right hemisphere visual and salience/ventral attention networks (RH Vis to RH Sal/VentAttn WMSC) was associated with higher epilepsy risk in FinnGen_R10_FE_STRICT (OR = 2.25, 95 % CI = 1.43-3.56, p < 0.01, FDR P = 0.019). Conversely, increased connectivity between left and right hemisphere salience/ventral attention networks (LH Sal/VentAttn to RH Sal/VentAttn WMSC) was linked to reduced epilepsy risk in FinnGen_R10_GE_STRICT (OR = 0.17, 95 % CI = 0.07-0.46, p < 0.01, FDR P = 0.033). A total of 15 nominally significant associations were identified across datasets. These findings suggest a causal relationship between white matter structural connectivity and epilepsy, offering insights into disease mechanisms and potential therapeutic targets.

Humans↗

PubMed2025

Causal relationships between antibody-mediated immune responses and acute pancreatitis: Evidence from a genetic study.

Certain specific antibody-mediated immune responses may be associated with acute pancreatitis (AP), but their causal relationship remains uncertain. Therefore, we used bidirectional two-sample Mendelian randomization (MR) to investigate their causal link and potential mediation by inflammatory cytokines. Data for this study were sourced from a large-scale Genome Wide Association Study (GWAS) communal data pool. To explore the causality between antibody-mediated immune responses and AP, we performed two-sample bidirectional MR analyses using 5 approaches: inverse-variance weighted (IVW), MR-Egger, weighted mode, weighted median, and simple mode. We also studied the potential mediating effect of 91 circulating inflammatory cytokines using a two-step MR method. Additionally, sensitivity analyses were conducted using MR-Egger intercept test and Cochran Q test to ensure the robustness of the outcomes. The results of forward MR analysis showed that anti-Epstein-Barr virus (anti-EBV) IgG seropositivity [OR = 0.941; 95% CI, 0.893-0.992; P = .023] and human herpes virus (HHV) 6 IE1A antibody levels [OR = 0.894; 95% CI, 0.816-0.981; P = .017] significantly reduced the risk of AP. The results of the reverse MR analysis revealed a negative correlation between AP and anti-EBV IgG seropositivity [OR = 0.775; 95% CI, 0.605-0.992; P = .043]. Furthermore, none of the 91 circulating inflammatory cytokines could mediate the causal relationship between HHV-6 IE1A antibody levels and the risk of AP. The results of sensitivity analysis confirmed the robustness of these causalities. The current study suggests that HHV-6 IE1A antibody levels are a protective factor against AP, and there is a bidirectional causality between AP and anti-EBV IgG seropositivity. In addition, the mediation analysis results showed that the 91 circulating inflammatory cytokines could not serve as mediators between the 46 antibody-mediated immune responses and AP.

Humans↗

PubMed2026

A causal relationship between chronic pancreatitis and cardiovascular disease: A two-sample Mendelian randomization analysis.

Current research suggests a link between chronic pancreatitis (CP) and cardiovascular disease (CVD), although the causality remains unclear. The aim of this study was therefore to conduct a 2-sample Mendelian randomization (MR) analysis to determine whether a causal relationship exists between CP and CVD. Summary-level data from publicly available genome-wide association studies of European populations were utilized for the MR analysis. Following quality control measures, independent single-nucleotide polymorphisms associated with CP and CVD were chosen as the genetic instruments. Four complementary MR methods were performed, namely the inverse variance weighted (IVW) method, weighted median, MR-Egger, and leave-one-out sensitivity. The IVW method revealed correlations between alcohol-induced CP and myocardial infarction (odds ratio [OR] = 1.001, 95% confidence interval [CI]: 1.000-1.002, P = .0010), as well as with large artery atherosclerosis stroke (OR = 1.067, 95% CI: 1.030-1.105, P = .0003). The IVW method also suggested that CP was significantly associated with stroke (OR = 1.040, 95% CI: 1.015-1.065, P = .0015) and with ischemic stroke (OR = 1.041, 95% CI: 1.005-1.078, P = .0024). These results remained robust and consistent in the sensitivity analysis. This MR study indicates a significant causal relationship between alcohol-induced CP and elevated risks of myocardial infarction and large artery atherosclerosis stroke, and a causal link between CP and stroke as well as ischemic stroke.

Mendelian Randomization Analysis↗

PubMed2026

The causal relationship between multiple cardiovascular diseases and glioblastoma: A Mendelian randomization study.

Observational studies suggest an association between glioblastoma (GBM) and cardiovascular diseases (CVDs), but a causal relationship remains unestablished. This study aimed to investigate the causal link between multiple CVDs and GBM risk. The inverse variance weighted method indicated that all 18 CVDs had significant causal associations with GBM (P < .05). Genetically predicted CVDs were uniformly associated with a lower risk of GBM (odds ratio < 1), identifying them as potential protective factors. Sensitivity analyses confirmed the absence of significant heterogeneity or horizontal pleiotropy, and the MR-Steiger test validated the correct causal direction. This Mendelian randomization (MR) study provides evidence that a range of CVDs are causally associated with a decreased risk of developing GBM. These findings suggest shared biological pathways and offer new insights for understanding GBM etiology. We conducted a 2-sample MR analysis using publicly available genome-wide association study data. GBM was the outcome, and 18 cardiovascular-related traits (including coronary artery disease, myocardial infarction, and venous thromboembolism) were exposures. Instrumental variables were single-nucleotide polymorphisms significantly associated with exposures (P < 5 × 10-8). The primary analysis used the inverse variance weighted method, supplemented with MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analysis, and MR-Steiger directionality test, were performed to ensure robustness.

Causality↗

PubMed2025

Mendelian randomization and FinnGen analysis of the causal relationship between 473 gut microbiota species and chronic sinusitis.

OBJECTIVE: To investigate the causal associations between Gut Microbiota (GM) and Chronic Sinusitis (CRS) using Mendelian Randomization (MR). METHODS: Genome-Wide Association Study (GWAS) summary statistics for 473 GM taxa were obtained from MiBioGen consortium. CRS data (22,099 cases vs. 371,520 controls) were sourced from the FinnGen R12 cohort. Causal effects were estimated via Inverse Variance-Weighted (IVW), MR-Egger, weighted median, and Bayesian-weighted MR methods. Sensitivity analyses (heterogeneity and horizontal pleiotropy tests) were performed to validate robustness. RESULTS: IVW analysis identified 20 GM taxa significantly associated with CRS risk (p < 0.05). Of these, 7 taxa (e.g., Francisellales, Roseibacillus, Merdibacter massiliensis) exhibited risk-increasing effects, while 13 taxa (e.g., Firmicutes I, Succinivibrionaceae) showed protective effects. Sensitivity analyses confirmed the absence of significant heterogeneity (Cochran's Q p > 0.05) or pleiotropy (MR-Egger intercept p > 0.05). Bayesian-weighted MR validated 18 causal relationships (posterior probability > 95%), except for RUG420 sp900317985 and UBA7703 (non-significant). CONCLUSIONS: This MR study provides genetic evidence supporting causal roles of specific GM taxa in CRS pathogenesis. These findings highlight the gut-sinus axis as a potential therapeutic target and underscore the utility of large-scale biobanks (e.g., FinnGen) in advancing precision medicine. LEVEL OF EVIDENCE: Level 5. Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

PubMed2025

Mendelian randomization reveals causal relationships between cytokines and male reproductive diseases.

This study aims to explore the causal links between cytokines and four male reproductive disorders, namely abnormal spermatozoa (AS), male infertility, erectile dysfunction (ED), and hyperplasia of prostate (HP), employing a two-sample Mendelian randomization (MR) approach. Genetic associations with male reproductive diseases were derived from the IEU OpenGWAS project, with cytokine data from two GWASs focused on the human proteome and cytokines. Estimations were derived using inverse variance weighting, MR-Egger regression, weighted median, weighted model, and simple mode. Furthermore, the robustness of the findings was evaluated through Cochran's Q-test, MR-Egger regression, and leave-one-out sensitivity analysis. Fifteen unique cytokines were identified as having causal relationships with the risk of four male reproductive disorders. Specifically, for AS, interleukin-22 (IL-22), IL-12, and macrophage migration inhibitory factor were negatively correlated with AS, while tumor necrosis factor β levels were positively correlated with AS. In the context of male infertility, IL-2 receptor antagonist levels, IL-34, and granulocyte-colony stimulating factor levels were positively linked to male infertility, whereas IL-21 showed a negative relationship. Regarding ED, IL-19, IL-1β, and eotaxin levels were negatively associated with ED risk, while macrophage inflammatory protein 1β (MIP-1β) levels and interferon gamma-induced protein 10 levels were positively associated. As for HP, stromal-cell-derived factor 1α levels and MIP-1α levels revealed negative associations with HP. In conclusion, this MR analysis revealed that several cytokines were causally associated with male reproductive diseases and could be valuable in offering new insights for further mechanistic and clinical investigations of cytokines-associated male reproductive diseases.

Male↗

PubMed2025

New insights into causal relationship between serum lipids, obesity, and asthma: a Mendelian randomization study.

OBJECTIVE: To identify causal risk factors for asthma using a Mendelian randomization (MR) approach. METHODS: Genetic variants associated with the exposures at the genome-wide significance level (p < 5 × 10 - 8) were obtained from corresponding genome-wide association studies. Summary-level statistical data for asthma were obtained from the UK Biobank (UKB) and the FinnGen Consortia. Univariate and multivariate MR analyses were performed to clarify causal relationships among obesity, serum lipids, and asthma. Meta-analyses were performed to combine UKB and FinnGen results using a fixed-effects model. RESULTS: In FinnGen, the odds for asthma increased for every 1-SD increase in body mass index (BMI; odds ratio [OR] 1.292, p = 1.34 × 10-7), together with body fat percentage (BF%; OR 1.449, p = 4.90×10-3), and total cholesterol level (OR = 0.949, p = 0.027). However, higher BMI and BF% were found to increase the risk for asthma in the multivariate MR analysis. In the UKB, the BMI results were replicated. Meta-analysis revealed that high-density lipoprotein cholesterol could also increase the risk for asthma, although there were no associations with other risk factors included in this study. CONCLUSION: This MR study found that genetically predicted higher BF% and BMI could increase the risk for asthma and corroborated some risk factors for asthma from previous MR studies. Moreover, the results suggest that higher BMI and BF% could serve as independent risk factors for asthma.

Humans↗

PubMed2026

The causal relationships and potential pathways between birth weight and cardiovascular diseases: A human genomics study.

The causal relationships and potential pathways between birth weight (BW) and various cardiovascular diseases (CVDs) remain unclear, particularly when discriminating maternal and fetal contributions of BW to CVDs. Leveraging the genome-wide association studies (GWASs) of BW (N = 321,223) and a range of CVDs (ncases = 43,676-181,522), we performed a 2-sample Mendelian randomization (MR) analysis to estimate the causal effect of BW, fetal-specific BW, and maternal-specific BW on coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and stroke. Furthermore, we applied a stepwise MR analysis approach to assess the potential involvement of childhood body mass index (CBMI) and age at menarche (AAM) in the causal pathways from BW to CVDs, while considering adult BMI. Finally, we performed colocalization analyses to justify the different biological mechanisms of maternal-specific and fetal-specific BW. The 2-sample MR analysis revealed that genetically predicted higher BW per standard deviation (SD) was associated with a decreased risk of CAD (odds ratio [OR] = 0.804, 95% confidence interval [CI]: 0.731-0.883), MI (OR = 0.720, 95% CI: 0.638-0.814), and stroke (OR = 0.900, 95% CI: 0.823-0.985), but an increased risk of AF (OR = 1.279, 95% CI: 1.160-1.410). Similar associations were observed for fetal-specific/maternal-specific BW. The stepwise MR analysis indicated that CBMI and AAM could serve as factors linking BW/fetal-specific BW and CVDs, albeit in different roles, by displaying an indirect causal effect through adult BMI. However, for maternal-specific BW, our results failed to support a causal effect on CBMI or AAM. Colocalization analyses supported the distinct biological mechanisms for maternal-specific and fetal-specific BW by showing different causal genes. The study suggested that both fetal genotype and intrauterine environmental exposure contribute to the causal associations. Additionally, AAM and CBMI may play a role in the pathways linking BW and CVDs, though the effect was only observed for fetal-specific BW.

Humans↗

PubMed2025

Causal relationship between educational attainment and the occurrence of venous thromboembolism.

BACKGROUND: The association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method. METHODS: Data mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data. RESULTS: Genetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR = 0.848; 95% CI 0.776-0.927; P = 2.84 × 10-4; UKB-VTE OR = 0.996; 95% CI 0.994-0.999; P = 0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. CONCLUSIONS: The MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.

Venous Thromboembolism↗

PubMed2026

Causal relationships between psoriasis and coronary artery disease: A two-sample Mendelian randomization study.

Previous studies have revealed a potential association between psoriasis and coronary artery disease (CAD). However, the causal relationship between the 2 remains unclear. This study aims to assess the causal link between psoriasis and CAD, which encompasses coronary heart disease, myocardial infarction, and angina pectoris. After obtaining genome-wide association studies data on psoriasis and CAD, we selected appropriate single nucleotide polymorphisms for Mendelian randomization (MR) analysis. The inverse-variance weighted method was used as the main analytical method. The inverse-variance weighted method indicated that psoriasis was associated with a higher risk of CAD (odds ratio = 11.538, 95% confidence interval = 4.498-29.595, P < .001), and coronary heart disease (odds ratio = 1.080, 95% confidence interval = 1.031-1.132, P = .001). Reverse MR analyses did not show causal effects of CAD on psoriasis. This study shows a significant causal association between psoriasis and incidence of CAD. However, there is no reverse causal association between CAD and psoriasis.

Psoriasis↗

PubMed2026

Causal Relationships Between Modifiable Risk Factors and Gastroesophageal Reflux Disease: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Gastroesophageal reflux disease (GERD) is a prevalent digestive disorder, yet the causal roles of modifiable risk factors remain unclear. This study aims to investigate the causal relationships between 28 modifiable risk factors (including obesity traits, mental health disorders, sleep traits, metabolic comorbidities, and serum parameters) and GERD using two-sample Mendelian randomization (MR). Gastroesophageal reflux disease (GERD). Our findings aim to inform targeted prevention and treatment strategies for GERD. METHODS: This study obtained data from extensive genome-wide association studies (GWAS). Pooled data associated with gastroesophageal reflux associations were obtained from the 23andMe Research team's research, which included a total of 129,080 cases of gastroesophageal reflux and 473,524 controls of European ancestry. We conducted a univariable Mendelian randomization (MR) analysis to ascertain whether genetic evidence of exposure demonstrated a statistically significant association with the risk of GERD. Subsequently, a multivariable MR analysis was carried out to estimate the independent effects of the exposures on GERD. RESULTS: Univariable MR analysis utilizing extensive GWAS data suggested that genetic factors such as BMI, Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), Attention Deficit and Hyperactivity Disorder (ADHD), Major Depressive Disorder (MDD), Schizophrenia, Negative emotions (including nervousness, anxiety, tension, or depression), Insomnia, Sleep apnea syndrome, Sleep duration, and Snoring, as well as Total cholesterol levels and Apolipoprotein B levels, are associated with the development of GERD. Multivariate Mendelian randomization of BMI and Negative emotion as correction factors showed that Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), ADHD, Insomnia, Sleep apnea syndrome, and Snoring were associated with an increased risk of GERD (p< 0.05). Conversely, longer sleep duration was associated with a reduced risk of GERD (p< 0.05). DISCUSSION: This MR study reveals novel causal mechanisms in GERD pathogenesis: (1) Peripheral adiposity (arm/leg fat mass) exerts independent effects beyond central obesity, indicating site-specific fat distribution significance; (2) ADHD emerges as a distinct psychiatric risk factor independent of mental disorders; (3) Sleep apnea operates through BMI-independent pathways. Collectively, these findings redefine GERD pathophysiology, highlighting fat depot specificity and brain-gut interactions as critical mechanistic drivers. CONCLUSION: Overall, our findings suggest that multiple risk factors are associated with the risk of GERD. These results provide a theoretical basis for controlling body weight and plasticity, improving sleep habits, and preventing and timely seeking medical attention to reduce the occurrence of psychiatric disorders, which will be important strategies to prevent and alleviate GERD.

Humans↗

PubMed2024

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. METHODS: The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. RESULTS: There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. CONCLUSION: Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

Humans↗

PubMed2025

Exploring the causal relationship between plasma proteins and postherpetic neuralgia: a Mendelian randomization study.

BACKGROUND: The proteome represents a valuable resource for identifying therapeutic targets and clarifying disease mechanisms in neurological disorders. This study investigated potential causal relationships between plasma proteins and postherpetic neuralgia (PHN). METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics from the Decode Genetics dataset (4,907 plasma proteins) and the FinnGen database (490 PHN cases and 435,371 controls). Instrumental variables (IVs) were selected based on relevance, independence, and exclusivity. Causal associations were assessed using inverse-variance weighted (IVW), MR-Egger regression, simple mode, weighted mode, and weighted median methods. Sensitivity analyses, including leave-one-out tests, evaluated result robustness, while colocalization analysis examined shared causal variants between traits. RESULTS: Eight plasma proteins showed significant associations with PHN (PFDR < 0.05). Higher levels of ATRN, PIANP, and CD48 correlated with increased PHN risk, whereas elevated KIR2DL5A, GPI, SEMG2, EIF4B, and HFE2 levels were associated with reduced risk. Sensitivity analyses supported these findings and excluded genetic pleiotropy as a major confounding factor. Colocalization analysis did not detect shared causal variants (PPH4 < 0.8). CONCLUSION: These results suggest a potential causal role for eight plasma proteins in PHN pathogenesis. While these proteins may serve as biomarkers or therapeutic candidates, further validation is required. This study advances understanding of PHN pathophysiology and supports future investigations into diagnostic and therapeutic strategies.

Mendelian randomization↗

PubMed2024

No causal relationship between glucose and inflammatory bowel disease: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Association between glucose and inflammatory bowel disease (IBD) was found in previous observational studies and in cohort studies. However, it is not clear whether these associations reflect causality. Thus, this study investigated whether there is such a causal relation between elevated glucose and IBD, Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a two-sample Mendelian Randomization (MR) with the independent genetic instruments identified from the largest available genome-wide association study (GWAS) for IBD (5,673 cases; 213,119 controls) and its main subtypes, CD and UC. Summarized data for glucose which included 200,622 cases and glycemic traits including HbA1c and type 2 diabetes(T2DM) were obtained from different GWAS studies. Primary and secondary analyses were conducted by preferentially using the radial inverse-variance weighted (IVW) approach. A number of other meta-analysis approach and sensitivity analyses were carried out to assess the robustness of the results. RESULTS: We did not find a causal effect of genetically predicted glucose on IBD as a whole (OR 0.858; 95% CI 0.649-1.135; P = 0.286). In subtype analyses glucose was also suggestively not associated with Crohn's disease (OR 0.22; 95% CI 0.04-1.00; P = 0.05) and ulcerative colitis (OR 0.940; 95% CI 0.628-1.407; P = 0.762). In the other direction, IBD and its subtypes were not related to glucose and glycemic traits. CONCLUSIONS: This MR study is not providing any evidence for a causal relationship between genetically predicted elevated glucose and IBD as well as it's subtypes UC and CD. Regarding the other direction, no causal associations could be found. Future studies with robust genetic instruments are needed to confirm this conclusion.

Humans↗

PubMed2026

Causal Relationship of Polyunsaturated Fatty Acids With Mental Disorders: A Systematic Review and Meta-analysis.

CONTEXT: Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options. OBJECTIVE: This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs. DATA SOURCES: Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs. DATA EXTRACTION: Two-sample MR technology was used to assess the role of PUFAs in MDs. DATA ANALYSIS: The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders. CONCLUSION: High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42024598472.

Humans↗