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PubMed2026

Potential mitochondria-associated pathogenic genes in sepsis: a multi-omics Mendelian randomization study.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of sepsis. However, human genetic evidence linking mitochondria-related genes to sepsis susceptibility remains limited. This study aimed to identify mitochondria-related genes associated with sepsis risk using a multi-omics Mendelian randomization framework. METHODS: Summary-data-based Mendelian randomization (SMR) was applied using sepsis genome-wide association study (GWAS) summary statistics from the UK Biobank and FinnGen databases. Expression, methylation, single-cell, and protein quantitative trait loci (QTLs) were used as genetic instruments. Colocalization analyses were conducted to evaluate whether SMR associations were driven by shared genetic variants. Expression of prioritized candidate genes was further examined in clinical septic samples, and correlations with disease severity (SOFA scores) were assessed. RESULTS: SMR analysis prioritized 13 mitochondria-related genes associated with sepsis risk. Immune cell-specific eQTL analysis suggested that genetically predicted SURF1 expression in memory B cells and naïve T cells was associated with sepsis risk. Differential expression of 12 candidate genes was confirmed in septic patients by qPCR, and PPOX expression showed a negative correlation with SOFA scores. Integration of mQTL and eQTL data supported a regulatory relationship between methylation at cg06661924 and AK4 expression. Increased genetically predicted AK4 expression was associated with higher sepsis risk (OR = 1.21, 95% CI 1.02-1.42). Protein-level analysis identified DUT as a potential sepsis-associated candidate, with consistent evidence across streptococcal and pneumococcal septicemia subtypes. Subtype analyses also suggested heterogeneous genetic signals across different sepsis subtypes. CONCLUSION: This study prioritized several mitochondria-related genes associated with sepsis susceptibility based on human genetic evidence. These findings provide candidate targets for further mechanistic and translational investigation.

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↗

PubMed2024

Dissecting the association between blood pressure traits, hypertension, antihypertensive medications and epilepsy: A Mendelian randomization study.

BACKGROUND: Observational studies suggest that hypertension and epilepsy have a high co-occurrence, and antihypertensive medications may have impacts on the prevention and treatment of epilepsy. However, the directionality of causation between them is elusive. METHOD: By leveraging genome-wide association studies (GWAS) summary data of each trait, we firstly performed bidirectional univariate Mendelian randomization (UVMR) to assess the strength and direction of the associations between pairs of traits, then multivariate MR (MVMR) was conducted to adjust for potential confounders in causalities. Cochran's Q statistics, leave-one-out analysis, MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO) were employed to evaluate the robustness of the results. Drug target MR was proceeded to assess the association between five classes of first-line antihypertensive medications and epilepsy. Specifically, single nucleotide polymorphisms (SNPs) extracted from GWAS data on systolic blood pressure (SBP)/diastolic blood pressure (DBP), along with expression quantitative trait loci (eQTL) were utilized as proxies for antihypertensive medications, respectively. RESULTS: Forward UVMR results provided evidence that genetically predicted blood pressure traits and hypertension have causal effects on epilepsy, while reverse UVMR indicated no causal impacts of epilepsy on blood pressure traits or hypertension. The sensitivity analysis results were robust. The causalities between DBP, hypertension and epilepsy remained remarkable after adjustment by MVMR. Inverse-variance-weighted MR (IVW-MR) yielded evidence of positive association only between Beta-Blockers target genes based on DBP GWAS screening and epilepsy. Summary-data-based MR (SMR) identified a positive correlation between Beta-Blockers target gene ADRA1D and epilepsy risk. CONCLUSIONS: Hypertension has a causal effect on epilepsy and managing DBP in patients with hypertension through Beta-Blockers may help prevent epilepsy.

Humans↗

PubMed2026

Programmed cell death and risk of diabetic retinopathy: a Mendelian randomization study.

BACKGROUND: Programmed cell death (PCD) plays an important role in diabetic retinopathy (DR); however, the underlying genetic mechanisms remain unclear. We used Mendelian randomization (MR) to investigate the causal relationships between PCD-related genes and DR. This study aimed to investigate the effects of PCD on the risk of DR by conducting MR analysis. METHODS: Summary statistics from gene expression quantitative trait loci (eQTL) studies (31,684 Europeans) were analyzed. Genetic instrumental variables were selected using cis-eQTL single-nucleotide polymorphisms (SNPs; P < 5 × 10- 8). Summary data-based MR (SMR) was employed to assess causal associations between PCD-related genes and DR, with three additional MR methods used for sensitivity testing. Bayesian colocalization was used to examine the shared regulatory mechanisms between PCD QTLs and DR risk loci. RESULTS: Sensitivity and colocalization analyses revealed six genes that affected DR: cathepsin H (CTSH), NAD(P)H: quinone oxidoreductase 1 (NQO1), tribbles pseudokinase 3 (TRIB3), and phosphoglycerate mutase 5 (PGAM5), which increased DR risk, and iron-responsive element binding protein 2 (IREB2) and tumor necrosis factor (TNF), which exhibited protective effects. Multivariate MR confirmed significant causal effects for CTSH, IREB2, and PGAM5 (p < 0.050). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (including 10 STRING-derived genes) revealed that 13 genes were enriched in necroptosis, apoptosis, mitophagy, and TNF signaling pathways in DR. CONCLUSIONS: This MR study supports the causal involvement of PCD in DR and identifies candidate genes (CTSH, IREB2, PGAM5, NQO1, TRIB3, and TNF) for therapeutic targeting or biomarker development in DR prevention or diagnosis.

Humans↗

PubMed2026

A 2-step, 2-sample Mendelian randomization study of gut microbiota, blood metabolites and dry age-related macular degeneration.

Dry age-related macular degeneration (dAMD) is the leading cause of blindness among elderly people in developed countries. The main objective of this study is to investigate the causal relationship between gut microbiota (GM), blood metabolites, and dAMD among European participants. Based on the genome-wide association analysis database, double sample Mendelian randomization (MR) analysis was performed on GM, blood metabolites, and dAMD. The inverse-variance weighted method is used to estimate the causal relationship between GM, blood metabolites, and dAMD, while multiple methods are employed to eliminate pleiotropy and heterogeneity. A 2-step MR analysis quantitatively assessed the effect of metabolite-mediated GM on dAMD. In MR analysis, 15 GM were found to be associated with increased or decreased risk of dAMD, and 18 blood metabolites were found to be associated with increased or decreased risk of dAMD. Our research also found that the potential association between GM and dAMD may be mediated by blood metabolite levels, specifically, ADpSGEGDFXAEGGGVR levels accounted for 38.9% of the causal pathway from genus Parasutterella to dAMD. Our research findings indicate that certain GM and blood metabolites can affect the onset of dAMD, and increasing the abundance of genus Parasottella can increase the risk of dAMD through the mediation of ADpSGEGDFXAEGGGVR levels.

Humans↗

PubMed2025

Causal association between 91 circulating inflammatory proteins and primary open-angle glaucoma: a bidirectional Mendelian randomization study.

BACKGROUND: Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach. METHODS: A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders. RESULTS: In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95 % CI: 1.04-1.21, P = 0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95 % CI: 1.06-1.36, P = 0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95 % CI: 1.02-1.16, P = 0.013), and stem cell factor (SCF) (OR: 1.09, 95 % CI: 1.03-1.15, P = 0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95 % CI: 0.82-0.95, P = 0.002), interleukin-18 (IL-18) (OR: 0.92, 95 % CI: 0.86-0.99, P = 0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95 % CI: 0.92-1.00, P = 0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95 % CI: 0.86-0.97, P = 0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95 % CI: 0.88-1.00, P = 0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95 % CI: 0.84-0.95, P = 4.63 × 10-4), IL-18 (OR: 0.93, 95 % CI: 0.89-0.97, P = 0.002), IL-18R1 (OR: 0.96, 95 % CI: 0.93-0.99, P = 0.023), and LIF (OR: 1.18, 95 % CI: 1.04-1.34, P = 0.013). Sensitivity analyses further supported the robustness of these findings. CONCLUSION: This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the precise biological mechanisms.

Humans↗

PubMed2026

Disentangling the association between chronic pain and sarcopenia-related traits: A bidirectional Mendelian randomization study.

ObjectiveThis study aimed to investigate the potential causal relationships between chronic pain and three key sarcopenia-related quantitative traits: (a) hand grip strength; (b) usual walking pace; and (c) appendicular lean mass, using bidirectional two-sample Mendelian randomization.MethodsWe conducted bidirectional two-sample Mendelian randomization using summary-level data from large-scale genome-wide association studies to assess the genetically predicted associations between chronic pain, including multisite chronic pain and chronic widespread musculoskeletal pain, and the aforementioned sarcopenia-related traits.ResultsMendelian randomization revealed that multisite chronic pain was significantly associated with an increased risk of low hand grip strength (odds ratio = 1.70; p < 0.001) and decreased usual walking pace (odds ratio = 0.81; p < 0.001); chronic widespread musculoskeletal pain was also significantly associated with decreased usual walking pace (odds ratio = 0.15; p < 0.001). Additionally, higher left hand grip strength was significantly associated with a lower risk of multisite chronic pain (odds ratio = 0.90; p< 0.001) and chronic widespread musculoskeletal pain (odds ratio = 0.99; p = 0.002); higher right hand grip strength was significantly associated with a lower risk of multisite chronic pain (odds ratio = 0.91; p = 0.002); and higher usual walking pace was significantly associated with a lower risk of multisite chronic pain (odds ratio = 0.49; p < 0.001) and chronic widespread musculoskeletal pain (odds ratio = 0.92; p < 0.001). No significant causal associations were detected for appendicular lean mass in either direction (all p > 0.05).ConclusionThis study provides genetic evidence supporting potential causal links between chronic pain and key phenotypic components of sarcopenia.

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↗

PubMed2026

Genetic Association Between Sleep Traits and Vertigo Risk: A Two-sample Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies suggest the potential association between sleep traits and vertigo; however, causal evidence remains limited. OBJECTIVE: This study aimed to explore the relationship between genetically predicted sleep traits and vertigo with the Mendelian randomization (MR) method. METHODS: Instrumental variables for sleep traits (snoring, sleep duration, insomnia, daytime sleepiness, daytime napping, and chronotype) were adopted from genomewide association studies (GWAS) data of European ancestry from UK Biobank. The summary-level datasets of vertigo were retrieved from the GWAS of FinnGen. Inversevariance weighted (IVW) method was adopted as the main analysis. RESULTS: IVW analysis revealed a significant association between genetically predicted daytime napping (OR = 1.51, 95% CI =1.08-2.12, P = 0.016) and chronotype (OR = 1.13, 95% CI =1.01-1.26, P = 0.033), both of which were associated with an increased risk of vertigo. However, we did not find evidence for a causal effect of snoring, overall sleep duration, long sleep duration, short sleep duration, insomnia, and excessive daytime sleepiness on vertigo. No reverse causality was detected. CONCLUSION: Our findings suggest that abnormal sleep patterns may serve as risk factors for vertigo disorders and offer opportunities for the prevention and management of vertigo disorders.

Humans↗

PubMed2026

Human skin microbiota and postpartum depression: A bidirectional Mendelian randomization study.

Postpartum depression (PPD) is a common mental health disorder after childbirth. Although microbiome research in PPD has mainly focused on the gut, the role of skin microbiota remains unclear. We used Mendelian randomization (MR) to assess potential causal associations between skin microbiota and PPD. A bidirectional 2-sample MR analysis used genome-wide association study (GWAS) summary statistics. Genetic instruments for skin microbial features were obtained from a published skin microbiota GWAS, and PPD data were derived from 67,205 mothers (7604 cases, 59,601 controls). Instruments were selected at P <1 × 10-5, linkage disequilibrium-clumped, harmonized, and filtered for weak instruments (F statistic <10). Because this microbiome threshold is exploratory, Benjamini-Hochberg false discovery rate correction was applied within taxonomic levels. The inverse-variance weighted method was primary, complemented by weighted median and mode-based methods. Heterogeneity, pleiotropy, and outliers were assessed using Cochran Q, MR-Egger intercept, and MR-PRESSO. Three skin microbial taxa showed nominal associations with PPD. Higher genetically predicted Acinetobacter on the dorsal forearm (dry skin; 9 single nucleotide polymorphisms [SNPs]; mean F = 22.12) and Proteobacteria in the antecubital fossa (moist skin; 6 SNPs; mean F = 23.44) were associated with increased PPD risk, whereas Betaproteobacteria in the antecubital fossa (11 SNPs; mean F = 21.54) was associated with decreased risk. Associations were directionally consistent, with no substantial heterogeneity or horizontal pleiotropy. After multiple-testing assessment, the findings were exploratory rather than definitive. Reverse MR did not support an effect of PPD on the identified skin microbiota. This MR study provides exploratory genetic evidence linking specific skin microbial features to PPD risk. The findings extend microbiota-related hypotheses beyond the gut microbiome but require validation in larger microbiome GWAS datasets, longitudinal cohorts, and mechanistic studies before clinical or causal conclusions are drawn.

Humans↗

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↗

PubMed2026

Limited evidence for causal effects of circulating inflammatory cytokines on the risk of selected hematologic malignancies: a two-sample Mendelian randomization study.

BACKGROUND: Hematologic malignancies have been linked to inflammatory cytokine levels; however, whether a causal relationship exists between inflammatory cytokines and hematologic malignancies remains uncertain. This study aimed to explore the causal association between inflammatory cytokines and hematologic malignancies using Mendelian randomization (MR) analysis. METHODS: Summary statistics from genome-wide association studies of 41 inflammatory cytokines, C-reactive protein, and selected hematologic malignancies were obtained from the UK Biobank, YFS, FINRISK, and FinnGen consortia. The inverse-variance weighted (IVW) method with false discovery rate (FDR) adjustment was used as the primary MR method. The weighted median, MR-Egger regression, MR-Robust Adjusted Profile Score, and MR pleiotropy residual sum, and outlier methods were used as supplied analyses. MR-Egger intercept estimates and Cochran's Q test were used to assess pleiotropy and heterogeneity. Leave-one-out analysis and the MR Steiger test were used to assess sensitivity and the direction of causality. RESULTS: Although the primary IVW analysis indicated that some inflammatory cytokines were associated with risk of selected hematologic malignancies, no significant causal relationship between cytokines and selected hematologic malignancies was detected after FDR correction. CONCLUSION: Genetically predicted cytokine levels did not have a significant effect on the risk of the selected hematologic malignancies. Further research is warranted to confirm the potential association between cytokine levels and the risk of selected hematologic malignancies.

C-reactive protein↗

PubMed2025

Genetic risk factors in rheumatoid arthritis: A Mendelian randomization study of chronic kidney disease in European populations.

Rheumatoid arthritis (RA) is a heritable autoimmune disease linked to chronic kidney disease (CKD) in observational studies. However, whether this association is causal and driven by shared genetic risk remains unclear, warranting genetic investigation. To investigate possible causal relationships between RA and different CKD subtypes, we used Mendelian randomization (MR) analyses with data from genome-wide association studies. The inverse variance weighted (IVW) methodology was the main method, and sensitivity analyses were added to improve the validity of the causal estimations. Our analysis predicted that RA significantly increases the risk of IgA nephropathy (IVW odds ratio [OR] = 1.041, 95% confidence interval [CI] = 1.018-1.065, P = 4.286e-04), diabetic nephropathy (IVW OR = 1.078, 95% CI = 1.009-1.152, P = .027), nephrotic syndrome (IVW OR = 1.164, 95% CI = 1.078-1.257, P = 1.012e-04), and chronic renal failure (IVW OR = 1.046, 95% CI = 1.018-1.075, P = 1.000e-03). MR analyses confirmed RA's positive causal effect on these CKD subtypes (all P < .05). While heterogeneity was observed for IgA nephropathy and chronic renal failure, sensitivity analyses (MR-Egger intercept, all P > .05) revealed no evidence of horizontal pleiotropy, supporting the robustness of our findings. Our findings suggest that in European-ancestry populations, a genetic predisposition to RA is causally associated with a higher risk of specific types of CKD. While these results require validation in diverse ethnic groups, they highlight the potential importance of renal monitoring for genetically susceptible RA patients, which may help mitigate the public health burden of CKD.

Humans↗

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↗

PubMed2024

Lipid-lowering drugs and risk of rapid renal function decline: a mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline. METHODS: In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline. RESULTS: The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003). CONCLUSION: Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline.

Mendelian Randomization Analysis↗

PubMed2024

Multiple sclerosis and abnormal spermatozoa: A bidirectional two-sample mendelian randomization study.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and previous observational epidemiological studies have suggested an association between MS and male infertility; male infertility due to sperm abnormalities may result from a number of aetiological factors, such as genetics, autoimmune factors, etc., and there are currently no studies to assess whether MS is associated with sperm abnormalities in men. Therefore, we performed a Mendelian randomization (MR) analysis to assess the causal relationship between MS and abnormal spermatozoa. METHODS: In this study, independent single nucleotide polymorphisms (SNPs) strongly associated with multiple sclerosis (MS) were identified by mining public genome-wide association study repositories and used as instrumental variables to explore causality. The causal effect of MS on sperm abnormalities was systematically assessed using two-sample Mendelian randomization (MR) techniques, and various analytical models such as inverse variance weighting (IVW), MR-Egger and MR-PRESSO were implemented to dissect the association. In addition, a wide range of sensitivity tests, including Cochran's Q test to detect heterogeneity, MR-Egger intercept analysis to assess bias, leave-one-out to test model robustness, and funnel plot analysis to detect potential publication bias, were implemented to ensure the robustness and reliability of the causal inference results. RESULTS: There was a significant causal relationship between MS and abnormal sperm (OR 1.090, 95% CI [1.017-1.168], p = 0.014); The accuracy and robustness of the results were confirmed by sensitivity analysis. CONCLUSION: Here we show that there appears to be a causal relationship between multiple sclerosis and abnormal spermatozoa. MS as a chronic disease has a higher risk of concomitant sperm abnormalities in its male patients, and reproductive and fertility issues in men with MS should receive special attention from clinicians.

Humans↗

PubMed2026

Causal relationships between somatic movement, brain structures, and mental well-being: A multi-stage Mendelian randomization study.

BACKGROUND: While the relationships between somatic movement, mental well-being, and brain health have been well established, the causal nature and underlying mechanisms of such associations remain incompletely understood. METHODS: By applying multi-stage Mendelian randomization to multi-source summary data derived from genome-wide association studies, we examined the causal effects of 4 somatic movement measures on 2 mental well-being indices and 13 types of brain structures, followed by testing the mediating roles of brain structures in accounting for the causal associations between somatic movement and mental well-being. RESULTS: Two-sample Mendelian randomization revealed that more physical activity was causally associated with greater mental well-being (life satisfaction and positive affect), while more sedentary behavior (longer leisure screen time and more sedentary behavior at work) with lower mental well-being. With respect to brain structures, sedentary behavior was causally linked to decreased volume, surface area, and local gyrification index in distributed cortical regions. Remarkably, decreased surface area of the piriform cortex was found to mediate the causal associations between sedentary behavior and lower mental well-being. CONCLUSIONS: Our findings not only complement and extend earlier reports on the associations of somatic movement with mental well-being and brain health by further resolving the causality but also help elucidate the neural mechanisms by which sedentary behavior adversely affects mental well-being.

Humans↗

PubMed2026

DNA Methylation, SERPING1 Expression, and Immune-related Traits in Osteoporosis: A Mendelian Randomization Study And Supportive Ex Vivo Evidence.

INTRODUCTION: Osteoporosis (OP) is a major public health burden; however, the role of SERPIN family proteins remains incompletely understood. This study aimed to investigate genetically inferred associations between SERPINs and OP and to explore potential regulatory relationships. METHODS: Genome-wide association study (GWAS) summary statistics were used to perform two-sample Mendelian randomization (MR) and summary-data-based Mendelian randomization (SMR) analyses. Primary MR estimates were derived using inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. Cancellous bone tissue from the greater trochanter of the femur was collected from three patients with OP and three non-osteoporotic controls. qPCR and WB were used to analyze the whole bone homogenate, IHC was used to detect decalcified bone sections, and mediation analysis was used to explore potential regulatory associations. RESULTS: Among the proteins of the SERPIN family, only SERPING1 had an obvious positive correlation with the risk of osteoporosis (OR = 1.06, P = 0.0012). qPCR, WB, and IHC analyses demonstrated increased SERPING1 mRNA and protein expression in bone tissue from OP patients. Mediation analyses suggested that cg15918732 DNA methylation may serve as an upstream regulatory factor for SERPING1 expression. In addition, the downstream associations also consist of the alteration of immune cell conditions, like the decrease in the quantity of natural killer cells and T cells, and the rise in the level of mononuclear cells, and so forth. DISCUSSION: These findings provide genetic evidence for the possible role of SERPING1 in OP, which may be achieved through epigenetic regulation and immune pathways. Due to the corresponding characteristics of genetic inference and the small sample size, these results are hypothetical and generative. CONCLUSION: This study shows that DNA methylation of cg15918732 may be associated with SERPING1 expression in osteoporosis and immune-related traits. These findings provide new insights into potential epigenetic and immunological pathways in osteoporosis, which may contribute to future mechanistic and translational research.

Humans↗