Aug 2026· Journal of International Medical Research· Vol 54· 0 citations· 40 references
Medicine
TL;DR
It is found that PHOSPHO1, BAIAP3, OSGIN2, and ZDHHC18 demonstrated statistically significant associations with hypertension risk after false discovery rate correction and should be prioritized for follow-up.
Abstract
Objectives Circadian rhythms regulate human health, and observational studies have linked their disruption to hypertension; however, confounding factors and reverse causality limit causal interpretation. We aimed to evaluate the existing evidence linking circadian gene sets and hypertension using Mendelian randomization. Methods Two-sample Mendelian randomization was performed using genome-wide association study summary-level data from non-overlapping European ancestry samples. Genetic variants of 1276 circadian genes (CGDB) were instrumental variables; the outcome was hypertension genome-wide association study data from the UK Biobank (ieu-b-5144; 463,010 participants). Single nucleotide polymorphisms were selected at p<5 × 10−8 (mean F-statistic: 276.5). Inverse variance weighting was the primary method used. Benjamini–Hochberg false discovery rate correction was applied across all 1276 genes. Sensitivity analyses were performed using heterogeneity testing, Mendelian randomization–Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, Steiger directionality testing, and leave-one-out analyses. Results Mendelian randomization identified 39 nominally significant associations (inverse variance weighting, p < 0.05). After false discovery rate correction, four genes reached statistical significance: PHOSPHO1 (odds ratio = 0.988, 95% confidence interval: 0.983–0.993), BAIAP3 (odds ratio = 1.009, 95% confidence interval: 1.005–1.014), OSGIN2 (odds ratio = 0.990, 95% confidence interval: 0.986–0.995), and ZDHHC18 (odds ratio = 1.012, 95% confidence interval: 1.007–1.018). The remaining nominal associations did not survive false discovery rate correction and were classified as exploratory. Functional enrichment implicated circadian rhythm, apoptosis, and glycosaminoglycan biosynthesis pathways. Sensitivity analyses did not reveal significant heterogeneity or pleiotropy. Conclusions These findings are hypothesis-generating and require experimental validation. PHOSPHO1, BAIAP3, OSGIN2, and ZDHHC18 demonstrated statistically significant associations with hypertension risk after false discovery rate correction and should be prioritized for follow-up. Other nominal findings should be interpreted as exploratory.
Background To investigate the potential causal relationship between inflammatory cytokines and type 2 diabetes (T2D) using two-sample Mendelian randomization (MR) and to explore the transferability of inflammatory genetic susceptibility in a Mongolian population through polygenic score (PGS) analysis. Methods A two-sample MR analysis was conducted using genome-wide association study (GWAS) summary statistics. Inflammatory cytokine data were obtained from protein quantitative trait locus GWAS datasets (GCST90274758–GCST90274848), and T2D summary statistics were derived from the IEU Open GWAS database (ebi-a-GCST006867). The inverse variance weighted method was used as the primary MR approach, complemented by sensitivity analyses. In an independent Mongolian cohort (N = 351), a PGS was constructed from directly genotyped cytokine-associated SNPs. We assessed PGS-T2D associations using logistic regression adjusted for age, sex, and principal components (PCs), with sensitivity analyses to determine the optimal PC number. Results In the European population, genetically predicted higher FGF-21 levels were associated with an increased risk of T2D (OR = 1.141, 95% CI: 1.032–1.261, P = 0.010), and IL-5 also showed a positive association with T2D risk (OR = 1.114, 95% CI: 1.004–1.237, P = 0.042). In contrast, ARTN, CD5, CSF-1, CXCL10, CXCL9, FGF-19, and SLAMF1 were associated with lower T2D risk. In the Mongolian population, the PGS for inflammation-related cytokine levels demonstrated a significant association with T2D status across models adjusting for 0 to 6 principal components (all P< 0.05). In the full model (adjusted for age, sex, and the first 4 PCs), each 1-SD increase in the PGS corresponded to a 25.4% increase in the odds of T2D (OR = 1.254, 95% CI: 1.005–1.575, P = 0.048; AUC = 0.625). These findings are suggestive and exploratory, necessitating further validation in independent cohorts. Conclusion This study identified nine inflammatory cytokines with potential causal associations with T2D in European populations. Notably, in a Mongolian cohort, a PGS for genetically predicted cytokine levels showed a modest yet independent association with T2D risk after controlling for population stratification. These cross-population findings warrant replication in larger-scale studies.
Cong Zhang, Yanping Zhao, Hui Pang et al.· Frontiers in Immunology· 0 citations
OBJECTIVE
This study used a bidirectional two-sample Mendelian randomization (MR) framework to investigate whether genetic liability to cardiac arrhythmias increases the risk of sepsis and whether genetic liability to sepsis increases the risk of cardiac arrhythmias.
METHODS
Summary statistics were obtained from publicly available genome-wide association studies in individuals of European ancestry. Cardiac arrhythmia data were derived from FinnGen (32,416 cases and 139,739 controls; IEU ID: finn-b-CARDIAC_ARRHYTM), and sepsis data were derived from UK Biobank (11,643 cases and 474,841 controls; IEU ID: ieu-b-4980). Independent single-nucleotide polymorphisms (SNPs) associated with each exposure at P < 5 × 10^-6 were selected, clumped at r^2 < 0.001 within a 10,000-kb window, harmonized, and filtered to retain instruments with F-statistics > 10. The primary analysis used random-effects inverse-variance weighting (IVW), with weighted median, MR-Egger, simple mode, and weighted mode analyses as complementary methods. Horizontal pleiotropy and outliers were assessed using MR-PRESSO and the MR-Egger intercept. Heterogeneity was evaluated with Cochran's Q test. Because the two causal directions were prespecified, false-positive control was strengthened by combining concordant directional evidence across methods with Benjamini-Hochberg false-discovery-rate assessment for the two primary IVW tests.
RESULTS
Genetic liability to cardiac arrhythmias was associated with a higher risk of sepsis (IVW OR = 1.066, 95% CI: 1.007-1.128, P = 0.0268). Genetic liability to sepsis was also associated with a higher risk of cardiac arrhythmias (IVW OR = 1.078, 95% CI: 1.005-1.156, P = 0.0347), although the reverse-direction analysis was based on only three SNPs and should be interpreted cautiously. Effect directions were concordant across complementary MR models, Cochran's Q test did not indicate substantial heterogeneity, MR-Egger intercepts did not support directional pleiotropy, and the two primary IVW tests showed an FDR-adjusted q value of 0.0536.
CONCLUSION
The present bidirectional MR analysis supports a robust association from cardiac arrhythmia liability to sepsis risk and suggests a possible reverse association from sepsis liability to cardiac arrhythmias. These findings support closer rhythm and infection surveillance in high-risk patients while highlighting the need for larger and biologically resolved validation studies.
Xinglei Li, Yadong Yang, Xunqi Zhang et al.· Journal of Cardiothoracic Su...· 0 citations
INTRODUCTION
Growth Hormone (GH) therapy for deficiency carries potential cancer risks with unclear causality. This Mendelian randomization study investigated the relationship between genetically predicted GH levels and cancer risk across 16 types.
METHODS
We selected genetic variants strongly associated with serum GH levels from published GWAS as instrumental variables. The primary analysis employed inverse-variance weighted MR, supplemented by MR-Egger regression. Sensitivity analyses, including MR-PRESSO and pleiotropy tests, were conducted to evaluate robustness. Mediation analysis was performed to assess the contribution of specific metabolites.
RESULTS
Genetic instruments for GH were derived from genome-wide association studies. Analyses suggested GH may be a risk factor for breast cancer, prostate cancer, and malignant lymphoma, and potentially a protective factor for oral/oropharyngeal cancer and skin cancer. Sensitivity analyses partially supported robustness, though notable limitations were present for some outcomes. Mediation analysis revealed that isovalerylglycine (mediating 34.12%) and the proline/trans-4- hydroxyproline ratio (28.40%) partially explained GH's effect on breast cancer, while the histidine/ glutamine ratio mediated 36.28% of GH's effect on prostate cancer.
DISCUSSION
These findings demonstrate tissue-specific effects of GH on carcinogenesis, partially mediated through metabolic pathways. Results suggest careful risk-benefit assessment in GH therapy and suggest metabolite monitoring could help mitigate cancer risk in susceptible individuals.
CONCLUSION
This Mendelian randomization study provides genetic evidence suggesting a potential causal role of GH exposure and the development of specific cancers, partially mediated by certain metabolites. GH shows both promoting and protective effects depending on the cancer type, with important implications for clinical management. The findings highlight the potential value of exploring risk-stratified approaches in GH replacement therapy and suggest further investigation into metabolic interventions to modulate GH-related cancer risk.
INTRODUCTION Type 2 diabetes (T2D) is a major global health burden with rising prevalence and significant morbidity and mortality. Smoking has been recognized as an independent risk factor for T2D, but the exact underlying mechanisms are not yet fully understood. METHODS We conducted a two-sample Mendelian randomization (MR) study to investigate the effects of smoking behaviors and smoking-related DNA methylation on type 2 diabetes (T2D) risk. This secondary analysis was based on publicly available summary statistics. Smoking traits were obtained from a large meta-GWAS of over 1.2 million individuals of European ancestry. DNA methylation data were derived from the CHARGE Consortium EWAS (n=15907) and mQTLs from the GoDMC (n=27750). T2D outcome data were obtained from a European GWAS including 74124 cases and 824006 controls. Replication was performed in FinnGen (17268 cases, 184778 controls) and BioBank Japan (40250 cases, 170615 controls). Stringently selected genetic instruments were applied, and causal effects were estimated primarily using two-sample MR with inverse-variance weighted analysis, complemented by MR-Egger and weighted median approaches, and further validated by colocalization analysis. RESULTS In our genomic analysis, we presented convincing evidence supporting the association between genetically predicted smoking initiation and an increased susceptibility to T2D. In epigenetic analysis, we identified methylation at 21 smoking-related CpG sites associated with T2D risk. Subsequently, 14 of these CpG sites were validated using the FinnGen dataset, and 12 of them were validated using the BBJ dataset. Furthermore, we observed strong colocalization evidence for four CpG sites, including cg23756272 (BCL2), cg03864215 (KCNJ11), cg09861057 (TDRD10) and cg10672416 (C12orf65), and T2D risk. CONCLUSIONS This research provides novel findings of the impact of smoking on T2D susceptibility, highlighting the role of epigenetic DNA methylation.
Wenhua Li, Yixiao Li, Pan Dong et al.· Tobacco Induced Diseases· 0 citations
This study indicates a genetic correlation and common risk genes, linking adiposity-related traits to PE-related diseases, and offers novel insights into the biological mechanisms underlying this comorbidity.
Yuping Shan, Hong Hu, Chong Liu et al.· Journal of Obstetrics and Gy...· 0 citations
Background/Objectives: Although genetic studies have linked immune phenotypes with anxiety, broad Mendelian randomization (MR) screens require explicit multiple-testing control. We reappraised 1753 reported immune-cell-trait-to-anxiety inverse-variance-weighted (IVW) association records available in the analysis tables and assessed the chromosome 20 signal that includes CD40. Methods: The reported records were derived from the 731-trait Sardinian flow-cytometry GWAS of Orrù et al. and were evaluated across one UK Biobank and three FinnGen anxiety phenotypes; outcome-specific Benjamini–Hochberg false-discovery-rate (FDR) correction was applied to the available analysis table. The leading locus was examined using bulk and single-cell expression quantitative trait locus annotations, two-sample MR, summary-data-based MR (SMR), HEIDI tests, and regional colocalization results. Results: Of 1753 tests, 120 were nominally significant, and 21 were retained after outcome-specific FDR correction (14 for UK Biobank anxiety and 7 for FinnGen all anxiety; none for generalized or phobic anxiety). B-cell and regulatory/CD4 T-cell traits were common among retained associations, and several B-cell traits mapped to variants at the CD40 locus. For FinnGen all anxiety disorders, monocyte instruments gave a positive estimate (beta = 0.00418, p = 9.25 × 10−4), whereas three naïve B-cell instruments gave a negative estimate (beta = −0.0520, p = 2.64 × 10−4). Monocyte SMR was null (p = 0.542). Naïve B-cell SMR was nominally significant (p = 0.00537), but HEIDI could not be calculated. Regional colocalization was weak in both cell contexts (PP.H4 = 0.0205 and 0.00272). Conclusions: The post-selection locus follow-up prioritizes a chromosome 20 immune locus but does not establish CD40-mediated regulation of anxiety. Because the upstream screen was not regenerated from source GWAS files and complete per-instrument F-statistics were unavailable, all findings are exploratory. CD40 remains a testable candidate for ancestry-matched fine-mapping and cell-state-specific validation.
Lu-Wei Wang, Yi-Fan Duan, Bo Sun et al.· Genes· 0 citations
