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PubMed2026

Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.

Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.

Humans↗

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

Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers.

BACKGROUND: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear. AIMS: We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers. MATERIALS AND METHODS: We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping. RESULTS: A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues. DISCUSSION: These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways. CONCLUSION: Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.

TWAS↗

PubMed2026

Integrative TWAS and multi-omics analyses prioritize HSPE1 as a candidate risk gene for bipolar disorder with immune cell-specific regulatory evidence.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with substantial disability. Although genome-wide association studies have identified multiple BD-associated loci, the underlying genes and mechanisms remain incompletely understood. METHODS: We integrated a European-ancestry BD genome-wide association dataset with cross-tissue and tissue-specific transcriptome-wide association studies (TWAS) and complementary gene-based analysis. Candidate genes were further evaluated using differential expression analysis, consensus clustering, immune infiltration analysis, machine learning, summary-data-based Mendelian randomization, Mendelian randomization using single-cell expression quantitative trait locus data, single-nucleus transcriptomics, phenome-wide association analysis, and virtual screening. RESULTS: The integrative analyses prioritized 37 candidate genes. Peripheral-blood differential-expression analysis identified 14 genes that remained significant after FDR correction, and their expression profiles separated BD samples into two expression-defined clusters. Machine-learning analysis selected UNC50, LMAN2L, LYG2, HSPE1, and KANSL3 for an exploratory classification nomogram. SMR associated genetically predicted higher HSPE1 expression with increased BD risk in two blood eQTL datasets. Cell-type-specific analyses indicated HSPE1-related associations in T-cell and natural killer cell subsets, while single-nucleus analysis descriptively showed higher HSPE1 expression in medial thalamic T cells from BD samples. PheWAS identified no genome-wide significant associations for HSPE1, whereas virtual screening identified candidate compounds with favorable predicted docking scores against the HSPE1 structure. CONCLUSION: This integrative multi-omics study identified HSPE1 as a candidate BD risk gene with immune-cell-related regulatory evidence, providing insight into BD pathogenesis and supporting functional validation.

Humans↗

PubMed2026

GWAS meta-analysis provides new insights into uveal melanoma risk.

OBJECTIVE: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. METHODS: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM's genetic architecture. RESULTS: We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10-8. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). CONCLUSIONS: This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.

Humans↗

PubMed2026

Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis.

Female reproductive disorders (FRDs), including polycystic ovary syndrome, endometriosis, uterine leiomyomata, and infertility, have been epidemiologically associated with impaired pulmonary function. However, it remains unclear whether this cross-organ link reflects shared genetic etiology and, if so, which cellular mechanisms mediate it. We performed a systematic genome-wide cross-trait analysis of three FRDs and lung function traits (FEV₁, FVC, FEV₁/FVC) using GWAS summary statistics from individuals of European ancestry, integrating genetic correlation, bidirectional causal inference, pleiotropy mapping, and single-cell enrichment analyses. We identified significant negative genetic correlations between FRDs and lung volume traits, most prominently for FVC (rg range: - 0.077 to - 0.178). Bidirectional causal analyses indicated that FRDs have a detrimental effect on lung volume, with higher FRD genetic liability associated with reduced lung volume. Cross-trait meta-analysis identified 17 pleiotropic variants across 11 loci, with the 19q13.2 (LTBP4) and 12q13.13 (HOXC6/HOXC9) loci showing strong evidence of shared causal variants. Critically, single-cell analyses revealed that shared genetic risk converged on mesenchymal lineages across organs, specifically alveolar adventitial fibroblasts in the lung and stromal/smooth muscle cells in the endometrium. Transcriptome-wide analyses further nominated the estrogen-responsive gene RERG as a convergent gene linking these conditions with lung function. Our study revealed a shared genetic architecture between female reproductive disorders and lung function traits, providing a basis for further mechanistic investigations and potential clinical evaluation. Furthermore, our findings suggest that shared fibroproliferative and hormone-responsive pathways may offer insights into the biological mechanisms underlying these conditions.

Female↗

PubMed2025

Tensor decomposition of multi-dimensional splicing events across multiple tissues to identify splicing-mediated risk genes associated with complex traits.

Identifying risk genes associated with complex traits remains challenging. Integrating gene expression data with Genome-Wide Association Study (GWAS) through Transcriptome-Wide Association Study (TWAS) methods has discovered candidate risk genes for various complex traits. Splicing, which explains a comparable heritability of complex traits as gene expression, is under-explored due to its multidimensionality. To leverage multiple splicing events in a gene and shared splicing across tissues, we develop Multi-tissue Splicing Gene (MTSG), which employs tensor decomposition and sparse Canonical Correlation Analysis (sCCA) to extract meaningful information from high-dimensional multiple splicing events across multiple tissues. We build MTSG models using GTEx data and apply them to GWAS summary statistics of Alzheimer's disease (AD) (111,326 cases and 677,663 controls) and schizophrenia (SCZ) (36,989 cases and 113,075 controls). We identify 174 and 497 significant splicing-mediated risk genes for AD and SCZ, respectively, at Bonferroni correction. For AD, our results demonstrate significant enrichment of AD related pathways and identify additional AD risk genes not detected in the single-tissue analysis, while preserving most top genes identified in the brain frontal cortex. Consistently, for SCZ, genes identified by our brain-wide MTSG model, built from a cluster of 13 brain tissues, exhibit stronger enrichment in SCZ-relevant genes and MTSG identifies unique SCZ risk genes compared to single-tissue models. These results showcase that our MTSG models capture distinctive splicing events across tissues, which might be overlooked when using single tissue alone. Our MTSG models can be applied to other complex traits to help identify splicing-mediated disease risk genes.

Humans↗

PubMed2026

Transcriptomic insights into exogenous fatty acid-enhanced halotolerance in Zygosaccharomyces rouxii.

BACKGROUND: High salinity restricts microbial growth during brine-based food fermentation. Although exogenous unsaturated fatty acids improve the salt tolerance of Zygosaccharomyces rouxii, the associated transcriptional mechanisms remain unclear. This study investigated the transcriptomic response of Z. rouxii CGMCC 3791 to palmitoleic acid (C16:1) under high salt conditions. RESULTS: Cells were cultured in yeast extract peptone dextrose (YPD) containing 120 g L-1 NaCl, with or without 20 μg mL-1 C16:1. They were analyzed by RNA sequencing. Principal component analysis clearly separated the two treatments. Using q < 0.05 and |log2 fold change| > 1, 23 differentially expressed genes were identified - three upregulated and 20 downregulated. INO1, MLS1, POX1, MEP2, and SOD5 were among the major responsive genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that peroxisome-associated functions, lipid metabolism, oxidative stress responses, nitrogen utilization, and mitogen-activated protein kinase (MAPK) signaling were the principal C16:1-responsive processes. CONCLUSION: Exogenous C16:1 elicited a focused transcriptional adjustment rather than broad transcriptome-wide reprogramming in salt-stressed Z. rouxii. The results indicated that peroxisome-linked lipid processes and redox regulation were candidate mechanisms underlying fatty-acid-associated halotolerance and provided targets for improving the robustness of high-salt food fermentation. © 2026 Society of Chemical Industry.

Zygosaccharomyces rouxii↗

PubMed2026

Suppression of HIV-1 replication in CEM-A cell cultures by trans-splicing group I introns targeting PAS/PBS sequences and conditionally expressing ΔN-Bax.

Anti-HIV group I introns containing antisense guide sequences directed against the HIV-1 primer activation signal and primer-binding site (PAS/PBS) were designed and evaluated. Because PAS/PBS sequences are present in the viral RNA species examined, these RNAs can serve as trans-splicing substrates. The introns were active against both artificial target RNAs and viral RNA generated during infection. Cleavage and degradation of targeted viral RNA may have contributed to suppression, whereas inclusion of a 3' exon encoding the proapoptotic protein ΔN-Bax was associated with increased programmed cell death and may have augmented suppression of viral replication. In cultured CEM-A cells, transgene expression of these introns markedly suppressed HIV-1 replication, with p24 levels falling below the assay detection limit in selected clones. RESULTS: RT-PCR and sequence analysis detected splice products containing the expected PAS/PBS junctions. In the dual-luciferase assay, intron expression reduced normalized Gaussia luciferase signal by approximately 70% relative to the negative control. Qualitative Annexin V imaging and caspase-3 assays were consistent with infection-dependent apoptosis after ΔN-Bax splice-product formation. Transient expression of each intron in HEK293T cells followed by infection with VSV-G-pseudotyped HIV-1NL4-3 at an MOI of 2 reduced p24 levels by approximately 50% at 4 days post-infection. Construct 128L produced the strongest RT-PCR band under the tested conditions and was selected for subsequent experiments. A canonical splice product and a low-abundance noncanonical splice product were detected; both involved the intended HIV-derived target RNA, although transcriptome-wide off-target splicing was not assessed. Heterogeneous transformed HEK293T populations showed an approximately 2-log10 reduction in p24. In selected clonal HEK293T and CEM-A lines, p24 was below the assay detection limit at the measured endpoints, including up to 90 days after infection in some CEM-A clones. CONCLUSIONS: PAS/PBS-targeting group I introns suppressed HIV-1-associated p24 production in the tested cell-culture models. Linking the introns to a ΔN-Bax 3' exon was associated with infection-dependent apoptosis and may further limit viral replication and spread. The use of highly conserved, functionally constrained target sequences may reduce the likelihood of escape, but viral evolution and transcriptome-wide off-target effects were not assessed. This conditional death-upon-infection strategy warrants further evaluation in primary-cell and in vivo models.

Humans↗

PubMed2026

Single-Cell Transcriptome-Wide Mendelian Randomization and Colocalization Uncover Potential Immunocytes-Related Therapeutic Targets for Obesity.

Weight-loss treatment is crucial for individuals with obesity to prevent various complications. The role of Immune cells in obesity has been recently recognized, whereas its translation into therapy requires identifying key target genes. We performed Mendelian randomization (MR) analysis to assess causal relationships between expression quantitative trait loci (eQTL) of 14 immune cells and obesity-related traits (obesity, body mass index and body fat percentage), and validated the results in colocalization analysis. For the putative causal genes identified by the MR and colocalization analyses, we conducted pathway enrichment, differential expressed gene (DEG) analysis and search of druggable evidence, and utilized a Tier system to prioritize drug targets for obesity. MR and colocalization evidence was observed for 1630 genes associated with one or more obesity-related traits, mainly expressed in CD4+ naive/central memory T cells and enriched in antigen processing and presentation pathways. Forty-one genes showed causal relationship with all three outcomes, among which 19 genes have not been reported for obesity previously. DEG analysis using single-cell RNA sequencing data of blood or adipose tissue indicated that the differential expression of UBE2Z in monocytes, ZCCHC7 in T cells, and FNBP4 in B cells between lean and obese individuals were consistent with the MR results. By searching drug-gene interaction databases, we found targeted drugs for PYGB and PRUNE1, and PYGB was the top gene ranked in the Tier system. This study provides evidence for the involvement of immune cells in obesity, and the potential cell-specific, immune-related targets for obesity treatment.

Obesity↗

PubMed2026

Integrative Multi-Omics Analysis Identifies Thrombosis-Associated Molecular Features Linked to Germline Susceptibility and Immune Cell Communication in Gastric Cancer.

Emerging evidence indicates that coagulation-related molecular programs are associated with thrombosis, tumor progression, and molecular dysregulation in gastric cancer (GC). However, thrombosis-associated molecular features in GC and their potential links to inherited susceptibility remain insufficiently understood. Integrated analyses of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were performed to identify thrombosis-associated genes and establish a machine learning-based prognostic signature. Genome-wide association study (GWAS), expression quantitative trait loci (eQTL), transcriptome-wide association study (TWAS), and Mendelian randomization (MR) analyses were conducted to investigate susceptibility-associated transcriptional programs in GC. Functional assays were used to evaluate candidate genes associated with malignant phenotypes. Single-cell RNA sequencing (scRNA-seq) and cell-cell communication analyses were further performed to characterize cell-type-specific expression patterns and potential intercellular interactions. A total of 22 differentially expressed thrombosis-associated genes were identified, and a prognostic signature comprising 14 genes was established. The signature stratified patients into high- and low-risk groups and showed prognostic performance in both the training and validation cohorts. Integrative GWAS, eQTL, and TWAS analyses identified susceptibility-associated transcriptional programs that were positively correlated with the thrombosis-associated risk score. Silencing ACTN2 and CRYAB significantly reduced GC cell migration and invasion. scRNA-seq analysis revealed relatively high CRYAB expression in neutrophils, and CellChat analysis suggested potential neutrophil-B cell interactions involving COLLAGEN-related signaling. This integrative multi-omics study identified a thrombosis-associated molecular signature linked to prognosis and germline susceptibility-associated transcriptional programs in GC. ACTN2 and CRYAB may represent candidate genes associated with GC cell migration and invasion, while single-cell analysis suggested potential immune-related communication features.

Humans↗

PubMed2026

Quantitative trait loci mapping of gene expression and chromatin accessibility in primary fibroblasts reveals shared allelic effects between Latin American and European ancestries.

BACKGROUND: Quantitative Trait Locus (QTL) analysis of molecular data has identified genetic variants associated with traits such as gene expression, and colocalization of these functional QTL with GWAS risk loci has offered insights into the genetic basis of human disease. We employed gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) obtained from human primary fibroblasts to investigate quantitative trait loci (QTLs) in cohorts ascertained for bipolar disorder of European (n = 150) and Latin American (n = 96) ancestries. RESULTS: Leveraging data from three countries of origin (The Netherlands, Colombia, Costa Rica) within our cohort, we characterized differences among individuals at the SNP, gene, and accessible-chromatin levels to compute ancestry-specific expression (e)QTLs and chromatin-accessibility (ca)QTLs. Across ancestries, we observed R2 ≥ 0.93 for eQTL effect sizes and R2 ≥ 0.95 for caQTLs, indicating a high degree of concordance. Integrating chromatin data with expression and genotype information enabled precise fine-mapping of eQTLs, yielding 203 genes with high-confidence (posterior probability > 90%) candidate regulatory pathways. In downstream analyses, transcriptome-wide (TWAS) and chromatin-wide (CWAS) association studies with brain- and skin-related GWAS identified 36 TWAS-significant genes and 77 CWAS-significant open chromatin regions. CONCLUSIONS: These findings underscore the shared genetic regulatory mechanisms across European and Latin American ancestries, while demonstrating that ancestry-specific reference panels enhance the accuracy of TWAS and CWAS in diverse populations. More broadly, this study highlights the value of paired multi-omic datasets from diverse cohorts for interpreting disease-associated genetic variation.

Humans↗

PubMed2026

Elevated intron retention implicates neuroinflammation in brains of individuals with alcohol use disorder.

Intron retention, a form of alternative RNA splicing, can occur as part of normal gene regulation or result from disruption of the splicing machinery. Retained introns can potentially form double-stranded RNA, activating innate immune sensors and inflammation. This mechanism has been implicated in cancer but has not been studied in neuropsychiatric diseases like alcohol use disorder. We systematically analysed transcriptome-wide intron retention events in post-mortem brain tissue from 142 individuals (66 with alcohol use disorder and 76 controls), encompassing 320 region-specific samples from the superior frontal cortex, nucleus accumbens, central nucleus and basolateral amygdala. Analyses were adjusted for demographic, technical and biological covariates. Validation was performed in alcohol-preferring (P) rats using long-read sequencing. In complementary experiments, immunofluorescent staining was used to detect double-stranded RNA in rat brain tissue, while single-cell RNA-sequencing was performed to test activation of double-stranded RNA-sensing pathways in human brains. Brains from individuals with alcohol use disorder showed significantly higher total intron retention compared with controls, independent of age, with females showing greater increases than males. A total of 368 introns were positively associated with alcohol use disorder, and these introns were significantly longer and had weaker splice acceptor sites compared with non-associated introns. Genes harbouring these intron retention events were enriched in Purkinje neurons, visual cortex neurons and oligodendrocytes. Computational predictions indicated these long introns could form duplex RNA structures. Increased double-stranded RNA was confirmed experimentally in multiple brain regions of alcohol-consuming rats, where it co-localized primarily with neuronal nuclei and dendrites. In individuals with alcohol use disorder, we found that multiple pathways including double-stranded RNA responses, neuroinflammation, interferon and NF-κB signalling, adaptive immunity and apoptosis were activated. In addition, NeuN-positive neuronal counts significantly decreased in both the prefrontal and visual cortices. Furthermore, single-cell analysis demonstrated upregulation of TICAM1, the target of double-stranded RNA sensor TLR3, in oligodendrocytes, as well as widespread activation of downstream inflammatory pathways across glial and neuronal cell types. These findings provide the first evidence that chronic alcohol consumption promotes an overall increase of intron retention in the brain and is associated with the presence of double-stranded RNA. Furthermore, the double-stranded RNA may contribute to neuronal loss and brain pathology by activating a neuroinflammatory response.

alcohol use disorder↗

PubMed2026

Functional characterization of the 9q34.13 locus identifies RAPGEF1 as a candidate gene modulating risk for melanoma and nevi via RAS activation.

Genome-wide association studies identified a melanoma- and nevus count-associated locus on chromosome band 9q34.13. Fine-mapping and melanocyte expression data collectively suggest two potential risk genes with opposite associations with risk: higher levels of Rap guanine nucleotide exchange factor 1 (RAPGEF1) and lower levels of uridine-cytidine kinase 1 (UCK1). Colocalization analyses and conditional transcriptome-wide association studies (TWASs) suggest multiple causal cis-regulatory sequence variants in partial linkage disequilibrium (LD) to each other. Melanocyte capture-HiC and CRISPR inhibition demonstrated regulatory interactions between fine-mapped variants and the RAPGEF1 and UCK1 promoters. Focusing on RAPGEF1, we demonstrate that RAPGEF1 expression promotes melanocyte growth and drives colony formation of human immortalized melanocytes. Following treatment with human epidermal growth factor (EGF), RAPGEF1 overexpression activated both RAP1 and RAS. Further, we show that RAPGEF1 expression is significantly enriched in melanomas that lack strongly activating RAS-MAPK pathway mutations, which suggests that RAPGEF1 may promote oncogenic RAS-MAPK pathway signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of RAPGEF1 expression in individuals whose melanomas lack RAS or BRAF mutations. Together with other recent studies, these data suggest that germline variation influencing RAS activation may play a key role in nevus development and melanoma risk.

GWAS↗

PubMed2026

Integrative genomic and transcriptomic analysis of hypertension in a Taiwanese population.

OBJECTIVES: Hypertension is highly prevalent in Asian populations and represents a major cardiovascular risk factor. However, most genome-wide association studies (GWASs) and transcriptome-wide association studies (TWASs) have focused primarily on Caucasian cohorts. This study aimed to identify genetic loci and gene expression signatures associated with hypertension in an Asian population. METHODS: We analyzed 10 739 hypertensive patients and 49 668 controls from the Taiwan Biobank, testing 4 512 191 genome-wide single nucleotide polymorphisms (SNPs). Integrated GWAS, TWAS, and expression quantitative trait locus (eQTL) analyses were conducted to characterize genetic risk. Additionally, a polygenic risk score (PRS) was constructed using a split-sample design to evaluate genetic risk stratification. RESULTS: We identified 14 loci significantly associated with hypertension, including a novel locus at 5p13.1. eQTL analysis linked this locus to DAB2 expression in whole blood. TWAS detected 55 hypertension-associated genes, with 20 (36%) overlapping GWAS loci. Several novel genes outside GWAS loci, including FBXL15, KCNIP2, and CRIP3, were highly significant and implicated in vascular biology and hypertension mechanisms. PRS analysis effectively differentiated hypertension risk, with individuals in the top 10% showing a > 3.5-fold increased risk compared to the bottom 10%. CONCLUSIONS: Our findings provide new insights into the genetic and transcriptomic landscape of hypertension in Asians. The identification of novel loci and genes advances understanding of disease biology and may guide precision medicine approaches for risk prediction and therapeutic development.

Female↗

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↗

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↗

PubMed2026

Identification of immune cell type-specific susceptibility genes in multiple cancers using transcriptome-wide association studies.

BACKGROUND: Transcriptome-wide association studies (TWAS) integrate gene expression and genome-wide association studies (GWAS) to identify disease susceptibility genes. Because gene expression varies substantially across cell types within tissues, cell type-specific prediction models may enhance the power of TWAS. METHODS: We conducted cell type-specific TWAS leveraging single-cell RNA sequencing data from the OneK1K cohort (14 immune cell types, 1.27 million cells) and GWAS summary statistics for 7 cancers (>290 000 cases in total). To improve prediction accuracy, we developed a modeling framework that incorporates shared gene expression effects across cell types. RESULTS: At a false discovery rate of 5%, we identified 106 (Bonferroni 5%: 13) previously unreported loci for breast cancer, 51 (4) loci for prostate cancer, 11 (4) loci for lung cancer, 39 (5) loci for melanoma, 9 (1) loci for ovarian cancer, and 2 (1) loci for diffuse large B-cell lymphoma, with most genes exhibiting cell type specificity. Gene set analyses confirmed joint associations of unreported genes with breast and prostate cancer risk in UK Biobank data. Additional lung tissue single-cell RNA sequencing data with 113 individuals validated 18 of 32 (56.3%) statistically significant genes for lung cancer. Across cancers, 139 statistically significant genes were shared by at least 2 cancer types and were primarily enriched in specific immune cell types. CONCLUSION: Cell type-specific TWAS improve the identification of novel cancer susceptibility loci and provide insights into the immune landscape of cancer etiology.

Humans↗