SEARCH · Search PubMed

Results for “Mendelian Randomization”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources

PubMed2025

Genome-Wide Aggregated Trans Effects Analysis Identifies Genes Encoding Immune Checkpoints as Core Genes for Rheumatoid Arthritis.

OBJECTIVE: The sparse effector "omnigenic" hypothesis postulates that the polygenic effects of common single nucleotide polymorphisms (SNPs) on a typical complex trait are mediated by trans effects that coalesce on expression of a relatively sparse set of core genes. The objective of this study was to identify core genes for rheumatoid arthritis by testing for association of rheumatoid arthritis with genome-wide aggregated trans effects (GATE) scores for expression of each gene as transcript in whole blood or as circulating protein levels. METHODS: GATE scores were calculated for 5,400 cases and 453,705 non-cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry. RESULTS: Testing for association with GATE scores identified 16 putative core genes for rheumatoid arthritis outside the HLA region, of which six-TP53BP1, PDCD1, TNFRSF14, LAIR1, LILRA4, and IDO1-were supported by Mendelian randomization analysis based on the marginal likelihood of the causal effect parameter. Five of these 16 genes were validated by a reported association of rheumatoid arthritis with SNPs within 200 kb of the transcription site, eight by association of the measured protein level with rheumatoid arthritis in UK Biobank, 10 by experimental perturbation in mouse models of inflammatory arthritis, and two-CTLA4 and PDCD1-by evidence that drugs targeting the gene cause or ameliorate inflammatory arthritis in humans. Fourteen of these 16 genes are in pathways affecting immunity or inflammation, and six-CD5, CTLA4, TIGIT, LAIR1, TNFRSF14, and PDCD1-encode receptors that have been characterized as immune checkpoints exploited by cancer cells to escape the immune response. CONCLUSION: These results highlight the key role of immune checkpoints in rheumatoid arthritis and identify possible therapeutic targets.

Humans↗

PubMed2026

Role of CD25hi CD45RA+ CD4 not Treg %T cell in mediating the effect of pyruvate fermentation to acetone on intrahepatic cholangiocarcinoma.

This study aimed to elucidate the potential correlation between gut microbiota and intrahepatic cholangiocarcinoma (ICC) by investigating their causal relationship, while also exploring the possible role of immune cells as mediators in this association. We first identified gut microbiota based on phylum, class, order, family, and genus level information. Using summary-level data from a Genome-Wide Association Study (GWAS), we performed a 2-sample Mendelian randomization (MR) analysis of ICC and gut microbiota. Furthermore, we used 2-step MR to quantify the proportion of the effect of immune cell-mediated gut microbiota on ICC. MR analysis identified pyruvate fermentation to acetone (PFA) as predicting ICC risk reduction. There was no strong evidence that genetically predicted ICC had an effect on PFA risk. Furthermore, the proportion of genetically predicted PFA mediated by CD25hi CD45RA+ CD4 not Treg %T cell (CCCTT) was 3% (95% CI: 0.93-5.03%). In conclusion, our study established a causal relationship between PFA and ICC. We observed that a minor fraction of this effect was mediated by CCCTT, while the majority of the impact exerted by PFA on ICC remains elusive. However, further investigations are warranted to elucidate the mechanisms underlying the influence of gut microbiota on ICC development.

Cholangiocarcinoma↗

PubMed2026

Probiotic potential of Parabacteroides johnsonii in mitigating age-related ovarian functional decline.

The gut microbiota is increasingly recognized as a regulator of reproductive health, yet its role in ovarian aging remains unclear. Here, we combine Mendelian randomization (MR) analysis with experimental validation to investigate the causal relationship between gut microbiota and ovarian aging. MR analysis identifies four microbial taxa significantly associated with age at natural menopause. In mouse models, germ-free mice exhibit accelerated ovarian functional decline, including reduced ovarian reserve and impaired folliculogenesis. Fecal microbiota transplantation (FMT) from young donors alleviates ovarian aging phenotypes, whereas FMT from aged donors exacerbates functional decline. Metagenomic analysis reveals species-level differences between young and ovarian-aging mice, with Parabacteroides johnsonii (P. johnsonii) enriched in young mice. Administration of P. johnsonii to middle-aged mice improves ovarian reserve, reduces follicular atresia, enhances granulosa cell proliferation, and decreases systemic inflammation. These findings highlight a causal role of the gut microbiota in ovarian aging and support microbiota-targeted interventions as a potential strategy to preserve ovarian function.

Female↗

PubMed2025

Integrative omics of the genetic basis for wheat WUE and drought resilience reveal the function of TaMYB7-A1.

Improving wheat drought resilience and water use efficiency (WUE) is critical for sustaining productivity under increasing water scarcity. Here, we integrate genome-wide association study (GWAS), expression quantitative trait locus (eQTL) mapping, population-transcriptome analysis, and summary-data-based mendelian randomization (SMR), followed by functional validation using indexed EMS mutants and transgenic lines, to systematically identify key WUE regulators. GWAS across water conditions in 228 accessions identifies 73 quantitative trait loci (QTLs) for WUE-traits. Transcriptome profiling of 110 diverse accessions reveals 28 drought-responsive modules. eQTL mapping uncovers 146,966 regulatory variants, including condition-specific hotspots associated with key drought-related pathways. Integrative analysis underscores 85 high-confidence candidate genes, notably TaMYB7-A1. Overexpression of TaMYB7-A1 enhances photosynthesis, WUE, root development, and grain yield under drought condition by activating TaPIP2;2-B1 (water transport), TaRD20-D1 (stomatal regulation), and TaABCB4-B1 (root growth), reflecting reduced water loss and improved physiological resilience. Our study presents a comprehensive regulatory map and robust targets for wheat drought adaptation and resilient cultivar breeding.

Triticum↗

PubMed2026

Role of IFIT1 and IFIT3 in systemic lupus erythematosus: modeling a diagnosis and exploring immune regulation.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by multi-organ involvement and a protracted clinical course. Current diagnostic strategies, which rely heavily on clinical symptoms and serology, are often insufficient for early detection. Therefore, highly accurate diagnostic biomarkers are urgently needed to facilitate early intervention and optimize personalized treatment strategies. D atasets GSE61635 and GSE135779 were integrated to identify differentially expressed genes. Weighted gene co-expression network analysis (WGCNA) was performed to isolate the module with the strongest clinical relevance. Mendelian randomization and single‑cell RNA‑seq were used to identify key disease‑relevant genes. A diagnostic model was then constructed, and gene set variation analysis (GSVA), along with gene set enrichment analysis (GSEA), was conducted to elucidate the underlying molecular pathways. IFIT1 and IFIT3 were identified as 2 core genes highly expressed in monocytes and T cells of SLE patients. Functional enrichment analysis revealed that these genes were enriched in immune-related pathways, metabolic pathways related to inflammation and genomic stability. The diagnostic model showed good accuracy, with an area under the curve (AUC) of 0.974 on the training set and 0.912 on the validation set. IFIT1 and IFIT3 represent promising biomarkers for diagnosing SLE and appear to mediate key immune and metabolic disturbances. Furthermore, the developed model serves as an accurate and reliable instrument for early diagnosis and personalized therapy. Large-scale clinical studies are warranted to further validate these findings and evaluate their clinical application.

Humans↗

PubMed2025

Association among blood pressure, antihypertensive drugs, and amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease. The impacts of antihypertensive drugs and blood pressure (BP) on ALS are currently debatable. OBJECTIVE: To evaluate the causal relationship involving antihypertensive drugs, BP, and ALS through a Mendelian randomization (MR) analysis. METHODS: The causal relationship between BP and ALS was evaluated by a bidirectional two-sample MR analysis. Then, a sensitivity analysis was performed using a secondary BP genome-wide association study. The drug-target MR was employed to evaluate the impact of antihypertensive drugs on ALS. Furthermore, we used cis-expression quantitative trait loci (cis-eQTLs) data from brain tissue and blood to validate the positive results by a summary-based MR method. RESULTS: We found that an increment in systolic BP (SBP) could elevate the risk of ALS (inverse-variance weighted [IVW] odds ratio [OR] = 1.003; 95% confidence interval [95%CI]: 1.001-1.006; per 10-mmHg increment) and ALS might be protected by angiotensin-converting enzyme inhibitors (ACEIs; OR = 0.970; 95%CI: 0.956-0.984; p = 1.96 × 10-5; per 10-mmHg decrement). A causal relationship was not observed between diastolic BP and other antihypertensive drugs in ALS. CONCLUSION: In the present study, genetic support for elevated SBP serves as a risk factor for ALS. Besides, ACEIs hold promise as a candidate for ALS.

Humans↗

PubMed2025

Evidence supporting the role of hypertension in the onset of migraine.

BACKGROUND: The association between hypertension and migraine remains unclear. OBJECTIVE: The aim of this study employ multi-layered evidence chain that revealed the association between hypertension and migraine. METHODS: We first strictly included data from the NHANES 1999-2004 population and applied logistic regression, subgroup analysis and RCS to assess the correlation between hypertension, SBP, DBP and migraine. Meanwhile, LDSC and Mendelian randomization were conducted based on the GWAS to determine the causal relationship between hypertension and migraine. Inverse-variance weighted (IVW) was used as the primary method. Sensitivity analysis and Colocalization analysis were performed to confirm the robustness of the results. LDSC validated the genetic correlation between traits. Enrichment analysis revealed their underlying biological mechanisms. RESULTS: After strict inclusion in NHANES, 10,743 participants were included. The logistic regression showed a significant correlation between hypertension (OR = 1.21 [95% CI, 1.08-1.36], FDR < 0.001)、DBP (OR = 1.01 [95% CI, 1.01-1.02], FDR < 0.001) and migraine. This association did not show significant group differences in subgroup. The MR results further supported the existence of a significant causal relationship between hypertension (OR = 1.77 [95% CI, 1.43-2.30], FDR < 0.001)、DBP (OR = 1.02 [95% CI, 1.01-1.03], FDR < 0.001) and migraine onset. Additionally, the RCS analysis showed a linear relationship (P non-linear = 0.897) between the two. The LDSC result showed a significant genetic correlation between the two (Rg = 0.1092, SE = 0.028, P < 0.001). CONCLUSION: The development of migraine caused by hypertension is mainly realized through high DBP.

Humans↗

PubMed2026

Genetic evidence supports the prioritization of CD40 among prespecified immune-related candidate drug targets in myasthenia gravis.

AIM: To prioritize prespecified immune-related candidate drug targets in myasthenia gravis for further validation based on integrated genetic evidence. METHODS: We integrated drug-target Mendelian randomization (MR) using cis-expression quantitative trait loci (cis-eQTLs), protein-level MR of plasma CD40 abundance using plasma protein quantitative trait loci (pQTLs), and colocalization analyses to evaluate genetically proxied associations with overall MG, early-onset myasthenia gravis (EOMG), and late-onset myasthenia gravis (LOMG). RESULTS: In this study, CD40 showed the most consistent genetic evidence among the six prespecified targets. Effect estimates are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Higher CD40 expression proxied by cis-eQTLs was associated with increased risk of overall MG (OR = 1.14, 95% CI: 1.05-1.24, Bonferroni-adjusted p = 0.022) and EOMG (OR = 1.32, 95% CI: 1.12-1.56, Bonferroni-adjusted p = 0.015). Genetically predicted higher plasma CD40 protein abundance was associated with increased overall MG risk (OR = 1.31, 95% CI: 1.08-1.57, Bonferroni-adjusted p = 0.010), whereas the protein-level MR result for EOMG was directionally consistent but not statistically significant. Colocalization analysis provided suggestive but not definitive evidence of colocalization between CD40 expression and EOMG risk. FCGRT, IL2RA, and SYK showed additional exploratory MR signals requiring further validation. CONCLUSION: CD40 showed the most consistent genetic support among the prespecified targets, supporting its prioritization for functional validation and further therapeutic investigation in MG.

CD40↗

PubMed2026

Genetic Basis of Pancreatic Steatosis: A Systematic Review of Comparison between African and Non-African Populations.

This systematic review compared genetic evidence of pancreatic steatosis across African and non-African populations to illuminate ancestry-specific mechanisms and precision-prevention opportunities. Following PRISMA guidelines for reporting, a search was conducted across PubMed, Scopus, Web of Science, and NHGRI-EBI GWAS Catalog for studies spanning 2011 to 31st March 2026. Eligible studies included genome-wide association studies (GWAS), polygenic risk score (PRS), and Mendelian randomization (MR) analyses that reported genetic associations with pancreatic fat phenotypes and had explicit ancestry stratification or comparison. Narrative thematic synthesis was performed due to methodological heterogeneity. Six core genetic studies (N > 120,000 participants) were included. The only multi-ethnic GWAS found a strong protective variant of African ancestry, rs73449607 (near PDX1/PLUTO), which reduced pancreatic fat (β = -0.67, P = 4.50 × 10⁻⁸) and explained 14.3% of the variance in African Americans (versus 5.3% overall). UK Biobank race-stratified PRS analyses confirmed the lowest pancreatic fat fraction in Black participants, with the strongest HbA1c PRS-fat association in this group (ρ = 0.23, P < 0.0001). European-dominant GWAS highlighted risk loci, including FUT2 rs601338 (higher fat and chronic pancreatitis risk, OR 1.26). MR studies demonstrated causal links between genetically predicted intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC) (OR 2.46 per SD) but not diabetes. African-ancestry genomes confer substantial protection against pancreatic steatosis, whereas non-African genomes are enriched for risk alleles that amplify the non-alcoholic fatty pancreas disease (NAFPD)-to-PDAC cascade. These ancestry-differentiated mechanisms position NAFPD as a precision medicine target.

Africa↗

PubMed2026

Is impulsivity simply a failure of self-control? Evidence based on multi-omics analyses of genomics, metabolomics and brain imaging.

High impulsivity-a hallmark of various adverse life outcomes such as substance abuse, impulsive buying, violence, and crime-has typically been considered as a failure of self-control. However, is impulsivity simply a failure of self-control? To address this issue, we employed multi-omics combined with brain imaging approach in a large-scale sample (Nbrain imaging=1524, Ngenomics=835, Nmetabolomics=946) to elucidate the relationship between impulsivity and self-control. Mendelian randomization showed a bidirectional association between impulsivity and self-control, suggesting that they influenced each other. Partial least squares analysis highlighted that self-control primarily implicates the frontal lobe regions (e.g., superior frontal gyrus), whereas impulsivity involves the amygdala, insula, and basal ganglia. The cerebellum, superior frontal gyrus, and middle frontal gyrus were identified as shared areas in impulsivity and self-control. Furthermore, gene-based association analysis identified heterochromatin protein 1 binding protein 3 as specifically related to impulsivity, while pathway enrichment analysis demonstrated that arginine and proline metabolism was a common metabolic pathway associated with both impulsivity and self-control. Overall findings demonstrate that impulsivity and self-control involve both shared and distinct brain regions, genetic and metabolic foundations. The brain imaging results suggest that impulsivity is related not only to self-control-related processes but also to the motivation to pursue rewards. Together, this large-scale integrative study firstly provides a side-by-side map of genomic, metabolic, and limbic-network signatures of impulsivity distinct from self-control, offering a foundation for mechanism-driven biomarker and intervention research in maladaptive impulsivity.

Impulsive Behavior↗

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗

PubMed2026

Multi-omics identification of therapeutic targets of compound sappan decoction in hepatocellular carcinoma.

BACKGROUND: Compound sappan decoction (CSD) is a multi-herbal traditional Chinese medicine formulation with clinical relevance in hepatocellular carcinoma (HCC). However, its therapeutic mechanisms remain unclear. METHODS: Bioactive compounds of CSD were identified and standardized using pharmacological and chemical databases. Potential targets were predicted via multiple target inference platforms. HCC-related genes were curated from comprehensive disease databases. Summary-data-based Mendelian randomization (SMR) was conducted to infer causal relationships between compound targets and HCC risk using large-scale quantitative trait loci (QTL) datasets and HCC genome-wide association study data. Colocalization analysis, protein-protein interaction (PPI) network construction, and GO/KEGG enrichment were performed on SMR-identified targets. Molecular docking evaluated binding affinities of representative compounds to prioritized targets. RESULTS: A total of 784 overlapping genes between predicted CSD targets and HCC-related genes were subjected to SMR analysis. Among these, 22 targets were significantly associated with HCC risk based on transcriptomic or proteomic QTLs and showed colocalization evidence. Notably, four targets (ADRB2, APOE, SYK, and PGF) were supported by both replication in an independent cohort and strong colocalization. These 22 targets were enriched in apoptosis, PI3K-Akt signaling, redox metabolism, and detoxification pathways. PPI analysis revealed central hubs including MMP9, BCL2, CASP1, and MCL1. Molecular docking demonstrated strong binding of APOE to quercetin, PGF to luteolin-7-olate, and SYK to kaempferol. CONCLUSIONS: CSD may exert therapeutic effects on HCC through modulation of genetically validated targets involved in tumor progression, inflammation, and metabolic reprogramming, supporting its potential clinical utility as an adjunctive treatment strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12672-026-04740-8.

Caesalpinia↗

PubMed2026

Integrated bioinformatics analyses for GSDMB in carcinogenesis and progression of bladder cancer.

BACKGROUND: Emerging evidence suggests that pyroptosis influences the development of various diseases. Gasdermin B (GSDMB), an intracellular protein that executes pyroptosis, has recently attracted attention for its potential role in tumor biology. However, its specific function in bladder cancer (BLCA) remains unclear. Therefore, this study aimed to investigate the potential role of GSDMB in the carcinogenesis and prognosis of BLCA patients. METHODS: Mendelian randomization (MR) studies were conducted to examine relationships between the expression of GSDMB and BLCA with expression quantitative trait loci (eQTL) data. Then, GSDMB mRNA expression data and clinical characteristics of BLCA patients were retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression was used to explore the relationship between GSDMB mRNA expression and patients' survival. Additionally, the correlation between GSDMB and the immune microenvironment, tumor mutational burden (TMB), tumor microenvironment (TME), and drug sensitivity in BLCA was examined. RESULTS: According to MR analysis based on eQTLs, GSDMB mRNA expression has positive causal effects on bladder carcinogenesis and the need for bladder surgery (P<0.05). The analyses of TCGA demonstrated an increased expression of GSDMB in BLCA tissues, correlating with improved patient survival. Additionally, elevated GSDMB mRNA expression was identified as an independent protective prognostic factor for BLCA, and it was associated with immune cell infiltration, TMB, TME score, and drug sensitivity. CONCLUSIONS: Elevated mRNA expression of GSDMB has a causal link to a higher risk of BLCA and the likelihood of bladder surgery, but also indicates a better prognosis. Thus, GSDMB exhibits dual effects and might serve as a potential biomarker for predicting onset and progression of BLCA. Nevertheless, further investigation of pathogenesis and mechanisms underlying GSDMB is warranted.

Bladder cancer (BLCA)↗

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↗

PubMed2026

Multi-omics integration and colocalization analyses prioritize candidate molecular loci associated with hypothermia.

BACKGROUND: Hypothermia is a life-threatening condition lacking specific pharmacological treatments. This study aimed to prioritize genetically supported molecular loci associated with hypothermia and to explore their pharmacological tractability using multi-omics data. METHODS: Initially, 2532 druggable genes were curated from the Drug-Gene Interaction Database and established literature. These were cross-referenced with cis-eQTL and cis-pQTL datasets, encompassing 870,655 and 114,281 SNPs for blood, respectively, alongside 2379 shared SNPs across adipose, skeletal muscle, and heart tissues. Matched instrumental variables were integrated with hypothermia GWAS summary statistics for two-sample Mendelian randomization (MR) and Bayesian colocalization. Transcriptomic differential expression analysis (DEA) was subsequently conducted as an exploratory analysis of cold-exposure-associated expression changes. Database-derived compound annotations were systematically re-evaluated according to target specificity, established pharmacological mechanism, and concordance with the direction of the MR estimates. RESULTS: Among 671 gene-level MR tests, 36 genes reached nominal significance, whereas only ABCC8 remained significant after FDR correction. Colocalization was evaluable for 8 of these 36 genes, and 4 loci (COL18A1, SLC1A7, ADIPOQ, and MERTK) met the prespecified PP.H4>0.90 threshold. The remaining 28 loci were not evaluable because sufficient overlapping regional variants were unavailable after harmonization. Transcriptomic analysis identified altered expression of SLC1A3 and SLCO4A1 under cold exposure, although these findings did not directly validate the colocalization-supported loci. Re-evaluation of database-derived compound annotations did not identify any direct, selective, and directionally concordant drug-repurposing candidate for hypothermia. CONCLUSIONS: COL18A1, SLC1A7, ADIPOQ, and MERTK showed colocalization support among the 8 evaluable nominal MR-associated loci. Because colocalization coverage was limited, these genes should be regarded as preliminary candidate loci rather than established therapeutic targets. The pharmacological annotations were indirect, non-selective, unsupported, or directionally inconsistent and should be interpreted solely as hypothesis-generating information.

Bayesian colocalization↗

PubMed2026

Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.

BACKGROUND: Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored. METHODS: We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting. RESULTS: We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (ADH1A, ADH1B, ADH4, ADH6) and ZNF827, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of ZNF827 in TAA and ADH6 in AAA at both mRNA and protein levels, corroborating the genetic predictions. CONCLUSION: This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.

MAGMA↗

PubMed2026

Identification of potential key genes involved in iron deficiency for sepsis: A retrospective cohort and transcriptomic study.

Iron overload has been associated with sepsis, but the role of iron deficiency and its molecular links remain unclear. We investigated the association between iron deficiency and sepsis and identified candidate genes potentially linking these conditions. MIMIC-IV data were used to assess the association between serum iron and sepsis status. Transcriptomic datasets from dietary iron-deficient mice (GSE10421), LPS-induced septic mice (GSE267388), and a human blood sepsis cohort (GSE137340) were sequentially analyzed to identify and externally evaluate candidate genes. IEU Open GWAS summary statistics were used for exploratory Mendelian randomization (MR). Exploratory drug prediction was performed using L1000FWD, followed by molecular docking analysis. Patients with sepsis had significantly lower serum iron levels, and restricted cubic spline analysis showed a nonlinear association between serum iron and the odds of sepsis. Cross-tissue transcriptomic analysis identified Sqle, Lss, and Rdh11 as candidate genes. In the human blood cohort, SQLE and RDH11 were significantly increased, whereas LSS was not significantly altered. Exploratory MR showed that genetically proxied SQLE expression was associated with higher odds of sepsis (odds ratio [OR] = 1.23, P = 1.67 × 10-3), whereas LSS expression was associated with lower odds (OR = 0.97, P = 8.90 × 10-4); RDH11 showed no significant association (OR = 1.01, P = .90). Drug prediction identified ML106 as the top-ranked candidate drug, and molecular docking predicted potential binding poses with SQLE and LSS. Serum iron showed a nonlinear association with sepsis status. SQLE, LSS, and RDH11 emerged as candidate genes, with concordant expression changes of SQLE and RDH11 observed in human blood. MR findings for SQLE and LSS were exploratory and require further validation. ML106 was identified through exploratory drug prediction and requires experimental validation before its therapeutic relevance can be established.

Sepsis↗

PubMed2026

Investigation of Fatty Acid Metabolism-Associated Molecular CPOX and the Underlying Mechanism in Follicular Lymphoma.

Dysregulated lipid metabolism is a key driver of follicular lymphoma (FL). This study aimed to explore the lipid metabolism-related genes (LMRGs) and clarify the underlying roles and mechanisms in FL. Bioinformatics methods, including differential analysis, WGCNA, machine learning, and Mendelian randomization, were utilized to select the LMRGs in FL. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to investigate the function of the key LMRG. Receiver operator characteristic (ROC) was used to evaluate the diagnostic value of the key gene CPOX. A pan-cancer analysis investigated CPOX's expression level and immune correlations. In vitro experiments using FL cell lines (WSU-FSCCL, DOHH2) validated CPOX expression, and CPOX knockdown in DOHH2 cells was used to assess its impact on viability, migration, invasion, and fatty acid metabolism. CPOX was confirmed to be a risk factor, significantly overexpressed in FL, and exhibited effective diagnostic ability in FL (AUC = 0.731). Functional analysis linked CPOX to mitochondrial function, oxidative phosphorylation, and heme metabolic process. Pan-cancer indicated the dysregulated CPOX across multiple cancers and closely correlation with immune characteristics. Experimentally, CPOX was higher in the more invasive DOHH2 cells; and CPOX knockdown suppressed FL progression and reduced lipid droplet formation, triglyceride, total cholesterol, and free fatty acid levels. In conclusion, this study fills the gap in understanding the significance of lipid metabolism-related molecules in FL, and innovatively proposes that CPOX is a risk factor for FL. Knockdown of CPOX inhibits the FL progression, which is regulated by fatty acid metabolism.

Lymphoma, Follicular↗