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PubMed2025

New evidence for the protective effect of gut microbiota regulation of ferroptosis-related proteins against osteoporosis.

Osteoporosis (OP), characterized by bone degradation and increased fracture susceptibility, constitutes a significant global health burden. Recent findings implicate gut microbiota and ferroptosis in the regulation of bone metabolism; however, causal evidence for the gut microbiota's influence on OP specifically via ferroptosis regulation remains to be established. This study employed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics to investigate these causal relationships and delineate mediating pathways.We assessed causal links between gut microbiota, ferroptosis-related proteins, and OP risk. Associations for gut microbiota abundance and ferroptosis-related proteins were derived from GWAS data and Icelandic blood-derived protein quantitative trait loci, respectively. Outcome data for OP were obtained from the FinnGen Release R12. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy.  MR analysis identified 33 gut microbial taxa causally associated with OP risk: 13 protective and 20 detrimental. Similarly, 34 ferroptosis-related proteins were categorized as protective (18) or detrimental (16) for OP. Mediation analysis revealed that the protective effect of Terrisporobacter othiniensis on OP is partially mediated by the ferroptosis regulator MDM4 (indirect effect β = -0.020, 95% CI: -0.068 to 0.029), accounting for 6.8% of the total effect. Sensitivity analyses showed no significant evidence of heterogeneity or horizontal pleiotropy. This study provides the first genetically validated evidence supporting a causal relationship between specific gut microbiota, ferroptosis-associated proteins, and OP susceptibility. Specifically, Terrisporobacter othiniensis demonstrates a novel protective mechanism, modulating OP risk partly through the ferroptosis regulator MDM4. These findings broaden understanding of the "gut-bone axis" and highlight the gut microbiota-ferroptosis pathway, particularly the MDM4/p53 axis, as a promising target for novel OP prevention and therapeutic strategies.

Ferroptosis↗

PubMed2026

Integrative multi-omics analyses suggest a candidate microbial metabolite-associated host gene network in ulcerative colitis.

Ulcerative colitis (UC) is associated with gut microbial dysbiosis, but the host molecular alterations potentially linked to microbially derived metabolites remain incompletely understood. We integrated Mendelian randomization (MR), microbial metabolite annotation, computational target prediction, colonic transcriptomics, network analysis, and machine learning. MiBioGen microbiome GWAS data were used as exposures and FinnGen Release 12 ULCERENTER as the outcome. Metabolites linked to MR-prioritized taxa were retrieved from GutMGene, and human targets were predicted using SwissTargetPrediction and SEA. UC-related genes were defined by integrating differential expression analysis and WGCNA and then intersected with predicted metabolite targets. MR prioritized one family and eight genera showing nominal genetically supported associations with UC, but none remained significant after Benjamini-Hochberg FDR correction. Three prioritized genera were linked to 15 microbe-metabolite records, corresponding to 13 unique metabolites; nine were retained for target prediction, yielding 277 unique predicted human targets. Transcriptomic analysis identified 1,530 DEGs and a 312-gene MEgrey60 module, with 273 overlapping genes, producing 1,569 unique UC-related genes. Their intersection with the 277 predicted targets yielded 47 candidate genes. Enrichment analyses highlighted mainly metabolic and lipid-related processes. Random Forest showed the highest mean AUC across the two independent external benchmarking cohorts, and SHAP prioritized EPHX1, HSD17B2, IGFBP5, and MMP10. IBDome analysis showed inflammation-associated expression differences in these genes. This study provides a genomics-informed, hypothesis-generating framework that prioritizes candidate microbe-metabolite-host relationships in UC for future experimental validation.

Humans↗

PubMed2026

Mitochondrial Function-Related Genes in Sleep Disorders: A Multi-Omics Mendelian Randomization Study.

Mitochondrial dysfunction is linked to sleep disorders in previous report, but the potential roles of specific genes remain unclear. This study aimed to dissect different subtype-specific genetic associations and their underlying mechanisms. A multi-omics Summary-data-based Mendelian Randomization (SMR) approach was performed to identify potential causal links between mitochondrial function-related genes and sleep disorders. We integrated GWAS data from FinnGen database (the discovery set), independent GWAS datasets (covering different sleep-disorder subtypes and used for validation), and cis-QTLs (including mQTLs, eQTLs, and pQTLs) to perform systematic exploration. Specially, we performed targeted validation of tissue-specific effects, leveraging gene expression data from disease-relevant brain regions within the GTEx database. Our SMR analysis identified mitochondrial function-related genes potentially modulating sleep disorders across biological layers, initially identifying 102 genes at the methylation level, 48 at the gene expression level, and 6 at the protein abundance level. Integrative analysis subsequently prioritized DCXR and ACADVL and revealed their distinct, subtype-specific associations. DCXR exhibited a protective role in sleep apnea while ACADVL showed a paradoxical risk conferring role in daytime sleepiness. In addition, the analysis identified an epigenetic regulatory mechanism for DCXR in which its expression and protein levels are modulated by DNA methylation. Finally, validation in brain-hypothalamus tissue confirmed DCXR as a significant potential protective factor (OR = 0.929, 95% CI: 0.887-0.973, P_HEIDI = 0.999, FDR = 0.2449). Our findings implicate key mitochondrial genes, particularly DCXR and ACADVL, in the pathophysiology of specific sleep disorder subtypes, highlighting potential avenues for precision medicine. Clinical trial number: Not applicable.

Humans↗

PubMed2025

Glutaryl-CoA dehydrogenase (GCDH) enhances renal malignancy risk via modulating glutarylcarnitine levels.

BACKGROUND: Crotonylation, a recently identified lysine acylation, plays a critical role in post-translational modifications [1]. It has been implicated in tumorigenesis by modulating metabolic reprogramming [2], DNA repair, immune evasion [3], and oncogenic signaling pathways, including PKA-FAK-AKT and androgen receptor signaling [4]. The specific role of crotonylation in renal malignancy (RM) remains poorly understood, especially in interaction with gene expression and metabolic pathway interactions. METHODS: This study integrates genome-wide association study (GWAS) summary statistics for RM from the FinnGen database, data on crotonylation-associated gene expression obtained from the eQTLGen consortium, and metabolite GWAS data obtained from the GWAS Catalog. A combined two-sample Mendelian randomization (MR), summary data-based Mendelian randomization (SMR), and mediation analyses were performed to investigate the causal link between Glutaryl-CoA dehydrogenase (GCDH) and RM, with a specific focus on glutarylcarnitine metabolism. RESULTS: MR analysis demonstrated a significant association; increased expression of GCDH is likely to increase the risk of RM (OR = 1.25, P = 0.0045). Mediation analysis revealed that elevated GCDH expression significantly reduced glutarylcarnitine (C5-DC) levels, which in turn was inversely associated with RM risk. A three-step MR-based mediation confirmed a significant mediating effect of glutarylcarnitine (β₁₂ = 0.0680, P = 0.002), with 30.25% of the total effect attributable to it. The robustness of these findings was further demonstrated by sensitivity analyses and SMR results. CONCLUSION: This study represents the first evidence that GCDH might exert an indirect pro-RM effect via the downregulation of glutarylcarnitine, thus providing new insights into tumor metabolic pathways and positioning glutarylcarnitine as a potentially diagnostic biomarker and therapeutic target for RM.

GCDH↗

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↗

PubMed2026

DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension.

BACKGROUND: Succinylation, a key post-translational modification, is implicated in the metabolic reprogramming and vascular remodeling of pulmonary arterial hypertension (PAH). While epigenetic regulation, particularly DNA methylation, potentially governs succinylation-related gene expression, its causal links to PAH remain unclear. METHODS: We performed an integrative causal analysis using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) to identify succinylation-related genes that influence PAH risk. We leveraged PAH GWAS data (FinnGen) and gene expression quantitative trait loci (eQTLGen). Subsequently, methylation-mediated effect decomposition was applied using DNA methylation data (GoDMC) to explore epigenetic regulation. Experimental validation was conducted in lung tissues from a monocrotaline (MCT)-induced PAH rat model via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Genetic analyses identified a significant causal effect of elevated Transgelin 2 (TAGLN2) expression on increased PAH risk. This effect was mediated by two specific DNA methylation sites, cg13892570 and cg16107628, which influenced PAH pathogenesis by regulating TAGLN2 transcription, with mediation proportions of 86.46 and 97.65%, respectively. Sensitivity analyses supported the robustness of these findings. Consistent with the genetic evidence, TAGLN2 mRNA was significantly upregulated in the lungs of MCT-induced PAH rats. CONCLUSIONS: This study establishes a clear epigenetic causal pathway in which DNA methylation regulates TAGLN2 expression to promote PAH. TAGLN2 is validated as a key disease driver and presents a promising target for diagnostic and therapeutic strategies in PAH.

Animals↗

PubMed2025

Alterations of gut microbiome in chronic rhinosinusitis: insights from a mendelian randomization study.

OBJECTIVE: Gut microbiome dysbiosis is associated with various diseases. Causal association between Chronic Rhinosinusitis (CRS) and gut microbiome is yet unknown. This study aimed to investigate the potential causal relationship between CRS and gut microbiome dysbiosis. METHODS: We used Genome-Wide Association Study (GWAS) data from FinnGen database for CRS. The Dutch Microbiome Project study provided data on gut microbiota species. A total of 334,182 individuals were included. Two-sample bidirectional Mendelian Randomization (MR) analysis was used to investigate causal relationship between CRS and gut microbiome. The main methods of evaluation were Inverse Variance Weighting (IVW), weighted median, weighted mode, and MR-Egger regression. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. RESULTS: Forward MR analysis indicated CRS is potentially linked to decreased risk of Haemophilus parainfluenzae (OR = 0.79, 95% CI 0.66‒0.94, p = 0.009) and increased risk of Bilophila's (OR = 1.14, 95% CI 1.02-1.27, p = 0.023) within the gut. Reduced risks in gut microbiota-related pathways like UDP-N-acetyl-d-glucosamine biosynthesis I (OR = 0.85, 95% CI 0.77‒0.94, p = 0.002) and increased risk in pathway NAD biosynthesis I from aspartate (OR = 1.14, 95% CI 1.03-1.27, p = 0.010) were also linked to CRS. Reverse MR analyses, we obtained no positive results (p > 0.05/412). CONCLUSION: This study reveals CRS exerts a causal impact on shifts within the composition of the gut microbiome and also links to the changes of gut microbiota-related metabolic pathways. The risk of changes in gut microbiota should be of greater concern in patients with CRS than in the general population. LEVEL OF EVIDENCE: Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

PubMed2026

Prioritizing Parkinson's disease risk-associated mitochondrial candidate genes via multi-omics integrative analysis.

BACKGROUND: Mitochondrial dysfunction has been implicated in Parkinson's disease (PD), but the genetically regulated mitochondrial genes associated with PD risk remain incompletely defined. METHODS: We conducted a summary-data-based genetic epidemiology study integrating summary-based Mendelian randomization (SMR), Heterogeneity in dependent instruments (HEIDI) filtering, and Bayesian colocalization to prioritize mitochondrial-related molecular features associated with PD risk. Mitochondrial-related genes were defined using MitoCarta3.0. Genetically predicted gene expression and plasma protein abundance were evaluated using expression quantitative trait loci (eQTL) data from eQTLGen and GTEx v8, and protein quantitative trait loci (pQTL) data was assessed using International Parkinson's Disease Genomics Consortium (IPDGC) as the discovery genome-wide association study (GWAS) and FinnGen as the replication dataset. Prespecified QTL analyses were interpreted using FDR correction, HEIDI filtering, and colocalization support. DNA methylation QTL analysis, mitochondrial phenotype MR, and single-nucleus RNA-seq analysis were performed as complementary analyses. RESULTS: In the primary eQTL analysis, higher genetically predicted TTC19 expression was associated with lower PD risk (OR = 0.80, 95% CI: 0.74-0.87, PPH4 = 0.80), whereas higher MALSU1 expression was associated with increased PD risk (OR = 2.21, 95% CI: 1.59-3.06, PPH4 = 0.96). Both associations survived FDR correction, passed HEIDI filtering, and showed colocalization support. GTEx whole-blood data supported the direction of the TTC19 association. No mitochondrial protein reached significance after FDR correction and colocalization filtering in the primary pQTL analysis. Complementary methylation analysis highlighted cg06270993 as an exploratory regulatory signal for MALSU1. CONCLUSIONS: This MR-colocalization study prioritizes TTC19 and MALSU1 as genetically supported mitochondrial-related candidate genes associated with PD risk. Further validation is required to define their functional roles in PD pathogenesis.

Humans↗

PubMed2026

Causal Relationships Between Oral Microbiota and Inflammatory Skin Diseases.

INTRODUCTION AND AIMS: The oral microbiome has been increasingly linked to systemic inflammation and immune dysregulation, but whether specific oral bacteria causally contribute to inflammatory skin diseases remains unclear due to confounding and reverse causation. This study aimed to assess the causal effects of 43 oral microbiota taxa on the risk of five inflammatory skin diseases using a Mendelian randomization (MR) approach. METHODS: We performed a two-sample MR analysis using genetic instruments for oral microbiota derived from publicly available genome-wide association studies and outcome data from the FinnGen consortium. Causal effects of oral taxa on systemic lupus erythematosus, vitiligo, pemphigus, localized scleroderma, and dermatitis herpetiformis were estimated. The inverse-variance weighted method served as the primary analysis, complemented by sensitivity analyses to evaluate horizontal pleiotropy, heterogeneity, and reverse causality. RESULTS: MR analyses identified several putative causal associations between oral microbiota and inflammatory skin diseases. Genus Granulicatella and an unknown Streptococcus species (ASV0009) showed causal effects on systemic lupus erythematosus. Family Lachnospiraceae_[XIV] and an unknown Rothia species (ASV0016) were associated with vitiligo. Five oral microbiota taxa demonstrated causal associations with pemphigus. Actinomyces species micronuciformis was linked to localized scleroderma. Order Fusobacteriales and an unknown Neisseria species (ASV0004) were associated with dermatitis herpetiformis. No significant heterogeneity or horizontal pleiotropy was detected in sensitivity analyses. CONCLUSION: This MR study provides genetic evidence supporting a causal role of specific oral bacteria in the development of several inflammatory skin diseases, highlighting the oral microbiome as a potential contributor to cutaneous autoimmunity and inflammation. CLINICAL RELEVANCE: Our findings highlight the putative role of the oral microbiome as a plausible candidate for mechanistic and clinical investigations into the prevention or adjunctive management of selected inflammatory skin diseases. However, oral hygiene improvement, targeted antimicrobials, and other microbiota-directed interventions were not directly tested in this MR study and remain hypothetical strategies requiring validation in experimental and clinical studies.

Humans↗

PubMed2026

Deciphering novel targets in salivary gland pleomorphic adenoma by integrating plasma proteomics and parotid transcriptomics analyses.

BACKGROUND/PURPOSE: Pleomorphic adenoma (PA) is the most common salivary gland benign tumor, with its molecular drivers elusive due to a lack of experimental models. This study aimed to decipher novel targets in PA by systematically integrating plasma protein quantitative trait loci (pQTL)-based Mendelian randomization (MR) with multi-omics profiling of parotid gland tissues. MATERIALS AND METHODS: We performed two-sample MR using 5450 plasma pQTLs and genome-wide association study summary for benign or broader salivary gland diseases from FinnGen consortium. Bulk RNA-sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) comparing PA to normal tissue were used for transcriptomic validation. Immunohistochemistry (IHC) was applied for protein-level validation in human PA, adenoid cystic carcinoma (ACC), and murine inflammatory lesions. RESULTS: MR identified 12 plasma proteins associated with benign salivary gland tumor risk. Transmembrane serine protease 6 (TMPRSS6) was the only protein significantly risk-increasing for both benign and broader salivary gland diseases. Strikingly, mitogen-activated protein kinase kinase 4 (MAP2K4) showed opposite MR effects between benign and all-lesion outcomes. Bulk RNA-seq showed limited concordance with MR findings, while scRNA-seq revealed a unique plastic epithelium and partially validated candidates at cellular resolution. Critically, IHC confirmed MAP2K4 protein overexpression specifically in human PA, but not in ACC or inflammatory lesions, while TMPRSS6 was downregulated in established pathologies despite its genetic risk association. CONCLUSION: By integrating plasma proteome-based causal inference with parotid tissue multi-omics, this study unveils MAP2K4 as a potential PA-specific driver. This integrative framework provides novel, context-specific targets for further functional investigation in salivary gland tumorigenesis.

Gene expression profiling↗

PubMed2026

Integrative post-GWAS analysis prioritizes immune regulatory pathways and candidate effector signals in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) has a complex polygenic architecture, but translating genome-wide association signals into biologically interpretable candidates remains challenging. We applied an integrative post-GWAS framework to refine SLE-associated loci and prioritize candidate regulatory mechanisms. METHODS: European-ancestry SLE GWAS summary statistics from FinnGen and Bentham et al. were meta-analysed, comprising 8417 cases and 354,277 controls. After quality filtering, 6,782,131 SNPs were retained. Downstream analyses included LAVA regional prioritization, Bayesian colocalization with GTEx v8 whole-blood and spleen eQTLs, independent replication in the Julià et al. Spanish cohort, pathway enrichment, bivariate LAVA cross-trait local genetic correlation, and therapeutic annotation. RESULTS: The discovery meta-analysis identified 46 genome-wide significant SLE-associated loci, including putative novel signals requiring database/literature qualification. LAVA identified 14 candidate index variants across 12 high-confidence regions, of which nine index variants were retained as the primary prioritized set based on LAVA support and/or convergent regulatory evidence. The strongest association mapped to the chr6p21.3/MHC region (rs389884), where four genes showed colocalization support, including CLIC1 in whole blood and C4A in spleen. Because the chr6p21.3/MHC rs389884 region lead variant was unavailable for replication and no suitable proxy was identified, this signal was interpreted as an emerging candidate for functional validation rather than a replicated causal signal. Seven available variants replicated with concordant effects. An exploratory Roadmap immune chromatin-state overlap analysis placed 15 of 45 non-MHC lead variants (33.3%) directly, and 34 of 45 (75.6%) within ±10 kb, in active immune enhancer/promoter states. Pathway analyses highlighted type I interferon, JAK-STAT signaling, cytokine regulation, and antigen presentation, while bivariate LAVA analyses supported shared local genetic architecture with rheumatoid arthritis, systemic sclerosis, and Sjögren syndrome. CONCLUSIONS: This integrative post-GWAS analysis refines SLE association signals into biologically interpretable candidate regions and supports interferon and JAK-STAT signaling as central genetically supported pathways in SLE.

CLIC1↗

PubMed2025

Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored. OBJECTIVES: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL. METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels ≤ 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen. RESULTS: Variants at 2 loci were associated (P < 5 × 10-9) with VWF:Ag levels ≤ 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels ≤ 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54). CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels ≤ 50 IU/dL, bleeding, and VWD.

Humans↗

PubMed2025

Genome-wide association studies in chronic venous disease: A systematic review.

BACKGROUND: Chronic venous disease (CVD) arises from venous hypertension secondary to impaired venous return, causing significant morbidity and diminished quality of life. Genetic factors are likely important in the pathogenesis and susceptibility of a patient to develop CVD. This systematic review summarizes genome-wide association studies (GWASs) that investigate the link between genetic variants and CVD. METHODS: A systematic review was conducted in accordance with the PRISMA guidelines, with the search dates ranging from January 1, 1994, to July 17, 2025. Abstract and full-text screening were completed by two independent reviewers, with any conflicts referred to a third senior reviewer. GWASs in adults investigating links between genetic variants and CVD were included. Exclusion criteria included patients with venous thromboembolism, arterial or diabetic disease, or animal models. RESULTS: Thirteen studies were included after screening 517 studies from a search of PubMed, EMBASE, and Ovid. Database sources included UK Biobank, FinnGen, PopGen, and country- or hospital-specific databases with a majority Caucasian and European patient cohort. A total of 602,760 patients were identified with varicose veins and 3,664,604 control cases that were studied with GWASs and other statistical methods including a two-sample Mendelian randomization approach, functional mapping, and genetic correlations. A variety of statistically significant genetic polymorphisms were identified that can be attributed to the heritability of varicose veins affecting inflammation and immunity (eg, PPP3R1, EBF1, and GATA2), hypertension (eg, CASZ1), and vascular architecture (eg, CASZ1, PIEZO1, and STIM2). Protective variants (eg, GJD3, MMP10, and 4EBP1) were also identified in Finnish populations. However, replication studies showed that these genetic polymorphisms are not generalizable to specific populations. CONCLUSIONS: This systematic review highlights genes contributing to the development of CVD that have been identified in the literature. An improved understanding of genetic contributions to the pathogenesis of CVD may inform future diagnostics, prognostics, and personalized treatment. Further larger scale studies representative of global populations, including meta-analyses of genome-wide association datasets, are required owing to individual GWASs being statistically insufficient to draw generalizable conclusions.

Humans↗

PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗

PubMed2024

Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations.

Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.

Humans↗

PubMed2024

Bidirectional association between abnormal cardiac conditions and epilepsy: A two-sample Mendelian randomization study.

BACKGROUND: Observational studies have consistently indicated a significant correlation between abnormal cardiac conditions and epilepsy. However, the association and direction of this relationship remain a subject of debate. This study employs a two-sample bidirectional Mendelian randomization (MR) approach to investigate the association between abnormal cardiac conditions and epilepsy. METHODS: Instrumental variables, represented by single nucleotide polymorphisms (SNPs) associated with epilepsy and various abnormal cardiac conditions, were derived from large-scale genome-wide association studies databases, including FinnGen and UK Biobank. Bidirectional MR analysis was conducted to estimate the association between epilepsy and abnormal cardiac conditions. Sensitivity analyses were performed using MR-Egger, weighted median, Inverse Variance Weighted, and MR pleiotropy residual sum and outlier methods. RESULTS: The forward MR analysis suggested a potential positive effect of atrial fibrillation and flutter (AF) and valvular heart diseases (VHD) on the risk of epilepsy. Conversely, the reverse MR analysis indicated that epilepsy might increase the susceptibility to AF, VHD, and heart failure. CONCLUSION: The findings support a bidirectional relationship between AF, VHD, and epilepsy, indicating that AF and VHD can elevate the risk of developing epilepsy, while epilepsy, in turn, can also increase the risk of developing AF and VHD. Furthermore, the study suggest that epilepsy may contribute to the development of heart failure. These results underscore the importance of screening for cardiac abnormalities in patients with epilepsy and vice versa, to better understand their clinical significance and potential as modifiable risk factors.

Humans↗

PubMed2025

Association of cancers with the occurrence and 28-day mortality of sepsis: a mendelian randomization and mediator analysis.

Observational studies have indicated an association between cancer and the occurrence of sepsis, with an increased risk of mortality in cancer-related sepsis. However, whether a causal relationship exists between the two remains unknown. Summary statistics of thirteen cancers from the largest available genome-wide association studies (GWAS) of GWAS catalog and FinnGen biobank were extracted for the MR analysis. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. Univariable, multivariable, and reverse MR analyses were employed to explore potential associations between cancers and sepsis and its 28-day mortality. Moreover, a two-step mediation MR analysis was performed to investigate independent positive causal relationships between cancers and sepsis and its 28-day mortality. In univariable Mendelian randomization (MR) analysis, significant causal relationships were found between genetically predicted lung cancer (OR = 1.17, 95% CI = 1.08-1.26, adjusted p = 0.001), squamous cell lung carcinoma (OR = 1.10, 95% CI = 1.02-1.18, adjusted p = 0.042), lung adenocarcinoma (OR = 1.12, 95% CI = 1.03-1.21, adjusted p = 0.032), small cell lung carcinoma (OR = 1.07, 95% CI = 1.02-1.12, adjusted p = 0.031), and sepsis. Subsequent multivariable MR analysis revealed that these three types of lung cancer were independently associated with the risk of sepsis. Additionally, a causal relationship was found between lung cancer and 28-day mortality from sepsis, while no causal link was observed between non-solid tumors and the onset or death of sepsis. Reverse MR analysis did not indicate a potential for sepsis to trigger the onset of cancers. Furthermore, TRAIL was found to have promotive effects on the occurrence and mortality of sepsis. Lung cancer causally correlates with increased sepsis occurrence and 28-day mortality, as evidenced by Mendelian Randomization analysis. Genetic predispositions enhance this risk, underscoring the potential of genetic profiling to guide early, precise sepsis interventions in these patients.

Humans↗

PubMed2025

Dietary antioxidants: a challenge or an opportunity for asthma? Genetic insights from a Two-sample mendelian randomization study.

BACKGROUND: Oxidative stress is crucial in the immune response and airway inflammatory process associated with asthma. While the relationship between dietary antioxidants and asthma remains debated in observational studies, this study uses two-sample Mendelian randomization (MR) to explore a potential causal link. METHODS: We acquired six distinct categories of absolute circulating antioxidants and five different types of metabolic circulating antioxidants from the most recent genome-wide association study data of the European population, including vitamin A (retinol), vitamin C (ascorbic acid), vitamin E (tocopherol), β-carotene, lycopene, and urate. The latest data regarding asthma was obtained from the FinnGen database. We utilized single nucleotide polymorphisms as instrumental variables to conduct five MR methods. To confirm the accuracy of the results, additional sensitivity analyses were performed to eliminate any potential confounding factors, such as heterogeneity and pleiotropy. RESULTS: MR and sensitivity analyses revealed an association between circulating urate and asthma, suggesting a potential increase in asthma risk (OR = 1.090; 95% CI = 1.030-1.150; p = 0.004). No causal relationship was found for other antioxidants. CONCLUSIONS: This MR analysis suggested that genetically determined circulating urate may increase asthma risk. Further large-scale randomized controlled trials and mediated MR analysis are needed to explore underlying mechanisms.

Humans↗