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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

Genome-Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early-Onset and Late-Onset T2D.

AIMS: Type 2 diabetes (T2D) is a heterogeneous disorder with substantial variation in age at onset (AAO). This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO-defined T2D subtypes. MATERIALS AND METHODS: Using 74 795 European-ancestry participants from the UK Biobank, we performed genome-wide association studies (GWAS) of relatively early-onset T2D (eoT2D; AAO < 55 years) and late-onset T2D (loT2D; AAO ≥ 70 years). We investigated subtype-specific genetic loci, SNP-based heritability, genetic correlations, Mendelian randomization (MR)-based relationships, polygenic risk scores (PRS) and phenome-wide association studies (PheWAS). Single-cell transcriptomic data from human pancreatic tissues were further used to evaluate cell-type-specific expression patterns of candidate genes. RESULTS: SNP-based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to β-cell function and insulin regulation, including SLC30A8 and IRS1. By contrast, loT2D showed a comparatively lipid-related genetic profile, featuring APOE-associated signals and expression patterns in immune-related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype-specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation. CONCLUSIONS: Extreme AAO-defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age-stratified genetic risk assessment.

Type 2 diabetes↗

PubMed2006

Science communication in transition: genomics hype, public engagement, education and commercialization pressures.

This essay reports on the final session of a 2-day workshop entitled 'Genetic Diversity and Science Communication', hosted by the CIHR Institute of Genetics in Toronto, April 2006. The first speaker, Timothy Caulfield, introduced the intersecting communities that promulgate a 'cycle of hype' of the timelines and expected outcomes of the Human Genome Project (HGP): scientists, the media and the public. Other actors also contribute to the overall hype, the social science and humanities communities, industry and politicians. There currently appears to be an abatement of the overblown rhetoric of the HGP. As pointed out by the second speaker, Sharon Kardia, there is broad recognition that most phenotypic traits, including disease susceptibility are multi-factorial. That said, George Davey-Smith reminded us that some direct genotype-phenotype associations may be useful for public health issues. The Mendelian randomization approach hopes to revitalize the discipline of epidemiology by strengthening causal influences about environmentally modifiable risk factors. A more realistic informational environment paves the way for greater public engagement in science policy. Two such initiatives were presented by Kardia and Jason Robert, and Peter Finegold emphasized that science education and professional development for science teachers are important components of later public engagement in science issues. However, pressures on public research institutions to commercialize and seek industry funding may have negative impacts in both encouraging scientists to inappropriately hype research and on diminishing public trust in the scientific enterprise. The latter may have a significant effect on public engagement processes, such as those proposed by Robert and Kardia.

Commerce↗

PubMed2005

Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease.

There is current interest in the associations of circulating inflammatory markers (C-reactive protein, fibrinogen, white cell count, albumin, erythrocyte sedimentation rate, the factor VIII:von Willebrand factor complex, the tissue plasminogen activator:plasminogen activator inhibitor type 1 complex, fibrin D-dimer) not only with prognosis in acute coronary syndromes and acute stroke, but also in prediction of cardiovascular events in the general population. Recent meta-analyses of long-term prospective studies have established their associations with coronary heart disease (CHD) events, which may be cause, consequence or coincidence. These markers are also associated in epidemiologic studies of general populations with many cardiovascular risk factors (which may confound their associations with CHD risk), and also with asymptomatic arterial disease (of which they be consequences: 'reverse causality'). The causality of their associations with cardiovascular events is questioned by their lack of specificity for risk of cardiovascular events; and by the lack of association of their functional genotypes with CHD in 'Mendelian randomized trials'. Hence, proof of causality awaits testing in randomized-controlled trials of long-term selective reduction by future agents. Markers are of little additional predictive value to current cardiovascular risk scores, and it is premature to advocate their use in screening for cardiovascular risk prior to careful evaluation of costs, risks, and benefits.

Biomarkers↗

PubMed2026

Conventional and Shared Genetic Association Analysis Between Diabetes Mellitus and Sensorineural Hearing Loss.

PURPOSE: This study aims to investigate the epidemiological and genetic associations between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) across different subtypes. METHODS: We analyzed 502,490 participants from the UK Biobank using multivariate logistic regression to examine the association between DM and SNHL, considering gender, age, and HbA1c levels. Genetic correlations and causality were examined by linkage disequilibrium score regression and bidirectional Mendelian randomization. Cross-trait meta-analyses identified shared loci between DM and SNHL, followed by gene annotation, functional analysis, and drug candidate exploration for the shared traits. RESULTS: Observational analysis revealed significant associations between DM and SNHL, consistent in subgroups based on age, sex, and certain HbA1c levels. A positive genetic correlation was found between type 2 diabetes mellitus (T2D) and SNHL (Rg = 0.0982, p = 0.0095) between T2D and SNHL, and four loci were identified, with ARHGEF28 and TCF7L2 prioritized as credible pleiotropic genes. Enrichment was indicated in glucose metabolism and organogenesis, with shared heritability in metabolic tissues and outer hair cells. Metformin was identified as potential drug candidates for the T2D-SNHL comorbidity. CONCLUSION: These findings progress our understanding of the epidemiological association, shared genetic basis, and potential therapeutic targets between T2D and SNHL, which might contribute to the management of their comorbidity.

Humans↗

PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗

PubMed2005

Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology.

Insulin-like growth factors (IGFs) play a fundamental role in somatic growth and cellular differentiation, metabolism and survival. Indeed, the processes linking nutrition, metabolism and growth are thought to involve a complex interrelation among insulin, growth hormone (GH), IGFs and their binding proteins (IGFBPs). However, accumulating data from both experimental and molecular epidemiological studies indicate that these growth factors may also be important in the pathophysiological processes underlying chronic disease, including type 2 diabetes mellitus, coronary heart disease and cancer. Experimental and observational studies suggest that higher levels of circulating IGF-I may increase risk of several cancers. By contrast, recent prospective epidemiological studies suggest that relatively higher IGF-I levels may reduce the risk of type 2 diabetes and coronary heart disease. However, these relatively small-scale observational studies are susceptible to chance, reverse causality and residual or unmeasured confounding. A 'Mendelian randomization' approach based on large-scale gene association and prospective observational studies might help determine the possible causal role of IGF-I and its binding proteins in the aetiology of type 2 diabetes, coronary heart disease and cancer.

Animals↗

PubMed2025

New Genetic Loci Implicated in Cardiac Morphology and Function Using Three-Dimensional Population Phenotyping.

BACKGROUND: Cardiac remodeling occurs in the mature heart and is a cascade of adaptations in response to stress, which are primed in early life. A key question remains as to the processes that regulate the geometry and motion of the heart and how it adapts to stress. METHODS: We performed spatially resolved phenotyping using machine learning-based analysis of cardiac magnetic resonance imaging in 47 549 UK Biobank participants. We analyzed 16 left ventricular spatial phenotypes, including regional myocardial wall thickness and systolic strain in both circumferential and radial directions. In up to 40 058 participants, genetic associations across the allele frequency spectrum were assessed using genome-wide association studies with imputed genotype participants, and exome-wide association studies and gene-based burden tests using whole-exome sequencing data. We integrated transcriptomic data from the GTEx project and used pathway enrichment analyses to further interpret the biological relevance of identified loci. To investigate causal relationships, we conducted Mendelian randomization analyses to evaluate the effects of blood pressure on regional cardiac traits and the effects of these traits on cardiomyopathy risk. RESULTS: We found 42 loci associated with cardiac structure and contractility, many of which reveal patterns of spatial organization in the heart. Whole-exome sequencing revealed 3 additional variants not captured by the genome-wide association study, including a missense variant in CSRP3 (minor allele frequency 0.5%). The majority of newly discovered loci are found in cardiomyopathy-associated genes, suggesting that they regulate spatially distinct patterns of remodeling in the left ventricle in an adult population. Our causal analysis also found regional modulation of blood pressure on cardiac wall thickness and strain. CONCLUSIONS: These findings provide a comprehensive description of the pathways that orchestrate heart development and cardiac remodeling. These data highlight the role that cardiomyopathy-associated genes have on the regulation of spatial adaptations in those without known disease.

Humans↗

PubMed2026

Proteomic Profiling of Pulmonary Function and Cardiovascular Disease Risk in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Pulmonary function is linked to cardiovascular disease risk; however, the underlying mechanisms remain unclear. We aimed to identify protein biomarkers associated with pulmonary function and examine their impact on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and all-cause mortality. METHODS: Data from White and Black Americans in the Atherosclerosis Risk in Communities study (visit 2: N=11 354, mean age=57 years; visit 5: N=3517, mean age=75 years), a prospective cohort, were analyzed. Linear regression assessed associations between protein levels and pulmonary function measures, including forced expiratory volume in 1 second and forced vital capacity. The impact of the identified proteins on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and mortality was estimated using logistic regression and Cox proportional hazards models. Pathway enrichment and Mendelian randomization explored underlying biological functions and causal effects. RESULTS: Of 4766 proteins analyzed, 364 were cross-sectionally associated with forced expiratory volume in 1 second (and forced vital capacity (false discovery rate<0.05). Ninety-four and 270 proteins had concordant positive and negative effects, respectively. Five pathways related to pulmonary and cardiac function were enriched. Of the 364 proteins, 112 were linked to all 4 outcomes, where 86 were associated with increased risk (odds ratio/hazard ratio [OR/HR], 1.05-1.42) and 26 with reduced risk (OR/HR, 0.69-0.96). Six proteins (STAT3 [signal transducer and activator of transcription 3], MIC-1 [growth differentiation factor 15], apoA-II [apolipoprotein A-II], TPST1 [protein-tyrosine sulfotransferase 1], integrin a1b1 [integrin alpha-I: beta-1 complex], and BLC [C-X-C motif chemokine 13]) showed potential inverse causal effects on with forced expiratory volume in 1 second and forced vital capacity, and integrin a1b1 demonstrated consistent inverse associations with chronic obstructive pulmonary disease, coronary heart disease, and heart failure risks. CONCLUSIONS: Proteins associated with pulmonary function may influence CVD risk. Six proteins, including integrin a1b1, represent promising targets for future interventions.

Aged↗

PubMed2026

Imaging and genomics in stroke.

Imaging after ischemic and hemorrhagic stroke may allow measurement of key phenotypes of injury and recovery for which targeted therapies are still lacking. Such imaging endophenotypes provide quantifiable and heritable biomarkers that can represent mechanistic aspects of disease processes better than clinical measures. Artificial intelligence is allowing extraction of these imaging biomarkers in large cohorts, which can be paired with genomic and other omics data. This will allow the evaluation of what genetic and other biologic variations impact stroke injury and recovery. Integration of these analyses with bioinformatics tools (such as Mendelian randomization and multi-trait analysis) could further dissect how stroke complications overlap with other biologic processes and how they may be causally linked to risk factors. Further work is required to confirm the translational impact of these methods in elucidating mechanisms and drug targets for stroke. However, global collaborations are accelerating analyses on large multi-ethnic stroke cohorts, with availability of imaging data facilitated by federally-funded repositories such as the Imaging Repository for the Cerebrovascular Disease Knowledge Portal (iCDKP).

Humans↗

PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗

PubMed2026

COVID-19 multi-omics reveal organ-specific responses and biomarkers.

OBJECTIVE: Post-COVID-19 syndrome is characterised by persistent immune dysfunction and multi-organ sequelae. This study aimed to characterise the systemic blood molecular landscape induced by SARS-CoV-2 infection and identify prognostic markers linked to skeletal muscle mass loss, a key driver of poor outcomes. METHODS: We enrolled 30 healthy controls and 307 COVID-19 patients, collecting 422 plasma samples for integrated proteomic and metabolomic profiling to investigate organ-specific molecular alterations in COVID-19. RESULTS: We comprehensively mapped the molecular landscape of COVID-19, encompassing immune, tissue-specific, and metabolic perturbations, and delineated their interactions. Focusing on organ-damage-related molecular patterns associated with disease progression and mortality, we found that skeletal muscle mass loss contributed to poor clinical outcomes of COVID-19 (p < 0.0001). Dysregulated arginine metabolism emerged as a key metabolic signature in fatal COVID-19 cases, with GLUL, GOT1, and citrulline showing significant correlation with skeletal muscle mass loss. Longitudinal analyses further revealed that reduced citrulline levels underlie the poor outcome of COVID-19 patients with muscle mass loss. These findings were robustly supported through multiple approaches: Mendelian randomization confirmed causal relationships between citrulline depletion, sarcopenia/fat-free mass loss, and COVID-19 mortality (p < 0.05), transcriptomic analyses of SARS-CoV-2-infected golden hamsters (GSE231910) provided additional support in enrichment of arginine biosynthesis (FDR < 0.05), and in vitro experiments further demonstrated that citrulline depletion promotes pro-inflammatory M1 macrophage polarisation — a key immunological feature of critical COVID-19. Leveraging these insights, we developed a skeletal muscle loss-specific prognostic prediction model for COVID-19 using GLUL, GOT1, and citrulline. This model effectively stratified patients into high- and low-risk groups (p = 0.035). CONCLUSION: Our study advances the understanding of COVID-19-induced organ pathophysiology and provides a foundation for developing targeted therapeutic strategies for post-COVID sequelae.

COVID-19↗

PubMed2026

Multiomics analysis reveals that senescent CXCL16+ macrophages promote lung adenocarcinoma progression through TGF-β signalling.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains a leading cause of cancer-related mortality worldwide. Although, immunotherapy has become a cornerstone of first-line treatment, only 20-30% of patients achieve a durable clinical benefit, largely because of the complexity and heterogeneity of the tumour immune microenvironment. Emerging evidence indicates that cellular senescence, particularly within immune cells, contributes to tumour progression by impairing antitumour immunity; however, its mechanistic role in LUAD remains incompletely understood. METHODS: We performed an integrative multiomics analysis incorporating genome-wide association studies (GWASs), bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics to characterize immune heterogeneity in LUAD. Cellular senescence was validated by performing staining for senescence-associated β-galactosidase and the canonical markers p16 and p21. SHAP analysis was applied to evaluate the contribution of CXCL16+ macrophages. Functional roles were assessed using coculture assays, in vitro and in vivo tumour models, orthotopic tumour implantation, and multiplex immunofluorescence staining of clinical specimens. RESULTS: A summary data-based on Mendelian randomization analysis integrating GWAS and TCGA data identified CXCL16 as a senescence-associated gene that is causally linked to the LUAD risk. Single-cell RNA sequencing revealed that CXCL16 is predominantly expressed in macrophages, and the pseudotime analysis together with β-galactosidase staining confirmed its association with macrophage senescence. Spatial transcriptomics and immunofluorescence staining showed the marked enrichment of CXCL16+ macrophages in LUAD tissues. The cell-cell communication analysis further revealed a strong association between the number of CXCL16+ macrophages and the activation of the TGF-β signalling pathway within the tumour microenvironment. Functionally, CXCL16+ macrophages promoted LUAD progression via TGF-β signalling, as validated in vitro and in subcutaneous and orthotopic tumour models. Molecular dynamics simulations additionally suggested that LUAD patients with high levels of CXCL16+ macrophage infiltration may exhibit increased sensitivity to bosutinib. CONCLUSIONS: CXCL16 promotes macrophage senescence, and senescent CXCL16+ macrophages drive LUAD progression through TGF-β signalling. These findings identify CXCL16+ macrophages as a biologically and therapeutically relevant immune cell population, highlighting a potential target for precision intervention in LUAD.

Humans↗

PubMed1991

Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs.

A susceptibility locus for schizophrenia in the 'pseudo-autosomal' region has been proposed on the basis of the reported excess of sex-chromosome aneuploidies (e.g. XXY and XXX) among patients with schizophrenia and the finding that schizophrenic sib-pairs are more often of the same than of the opposite sex. This hypothesis has been tested in 83 sibships with two or more siblings fulfilling Research Diagnostic Criteria for schizophrenia or schizoaffective disorder. Alleles at the pseudo-autosomal telomeric locus DXYS14, which is unlinked with sex, were analysed using the method of affected sib-pairs. Affected sibs shared alleles at DXYS14 more frequently than expected by random Mendelian assortment, supporting genetic linkage between DXYS14 and schizophrenia.

Alleles↗

PubMed2026

Epigenetics and childhood obesity: DNA methylation coordinates environment and gene regulation.

Childhood obesity is a complex disorder which results from the combined contribution of genetics, the environment, and development, which is programmed and coordinated by epigenetic mechanisms. Of them, DNA methylation has emerged as an important molecular interface between environmental inputs and changes in gene expression. In this review, we provide an overview of the role of DNA methylation in childhood obesity during the key developmental stages, from prenatal life and childhood to adolescence. We also highlight the available evidence from candidate genes and genome-wide association studies implicating critical loci involved in energy homeostasis and adipogenesis, where DNA methylation is altered. Further, we also provide an overview of how maternal obesity, nutritional status, and bariatric surgery shape offspring's methylation profiles and contribute to the increased risk of programming obesity across generations. Although aberrant methylation patterns are consistently associated with altered metabolic phenotypes, disentangling causality remains a significant challenge. Herein, we highlight emerging approaches, such as rigorous longitudinal cohorts, epigenetic Mendelian randomization, and CRISPR-based epigenome editing, that are beginning to provide the analytical clarity needed to move beyond association. Finally, we examine the potential of DNA methylation signatures to inform early risk stratification and prevention possibilities. Although yet to be clinically validated, whole-genome methylation profiling is increasingly integrated with systems biology and multi-omics frameworks, making the identification of robust, clinically actionable markers more promising. A more precise understanding of how epigenetic processes shape susceptibility to childhood obesity could ultimately support strategies capable of altering lifelong metabolic trajectories.

Humans↗

PubMed2026

Shared genetic architecture of smoking dependence and Crohn's disease: A cross-trait analysis of GWAS summary statistics.

INTRODUCTION: Smoking dependence (SD) and Crohn's disease (CD) are epidemiologically associated, but whether this relationship reflects shared genetic susceptibility remains unclear. METHODS: We conducted a cross-trait genetic analysis of SD and CD using publicly available genome-wide association study (GWAS) summary statistics from European-ancestry populations. Genome-wide genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Pleiotropic variants were identified using PLACO and mapped to genomic loci using FUMA. Regional signal sharing was assessed by Bayesian colocalization. Functional analyses included stratified LDSC, Multi-marker Analysis of GenoMic Annotation (MAGMA), GTEx tissue analysis, and Metascape. Expression-linked candidate genes were prioritized using expression quantitative trait locus (eQTL)-based summary-data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) testing. Genetically informed spatial mapping of cells for complex traits (gsMap) was used for spatial mapping. RESULTS: SD and CD showed positive genetic correlation by LDSC (rg=0.2090, p=0.0008) and HDL (rg=0.3817, p=0.00106). PLACO identified 81 genome-wide significant pleiotropic SNPs, which were mapped by FUMA to three loci at 1p31.3, 5p13.1, and 12q12, represented by rs11209031, rs1395152, and rs17467116, respectively. MAGMA identified 22 FDR-significant genes, four of which remained Bonferroni significant: LRRK2, TNFRSF6B, ZGPAT, and RP4-583P15.15. Cross-trait tissue analysis showed significant enrichment of the shared genetic signal in whole blood and small intestine, while gene-set analysis highlighted inflammatory response (pbon=1.86×10-5) and T-helper 17 cell differentiation (pbon=7.37×10-4). SMR/HEIDI analysis further prioritized RPS6KB1 as a shared expression-linked candidate. Spatial mapping revealed a prominent signal in the embryonic gastrointestinal tract and gene-specific regional patterns involving LRRK2 and SLC2A13 in the adult mouse brain. CONCLUSIONS: SD and CD showed measurable shared genetic susceptibility, with convergent evidence from pleiotropic loci, immune-inflammatory pathway enrichment, tissue-level associations, and spatial transcriptomic mapping.

Crohn's disease↗

PubMed2026

Longitudinal Repeated Protein Measurements in a Multiethnic Cohort Identify Novel Diabetes Biomarkers That Reveal Unique Disease Pathways.

There is up to a fourfold increase in diabetes biomarkers identified with longitudinal repeated versus single time point proteomic measurements. The increase in biomarkers identified with longitudinal repeated measurements is supported by a similar proportion being nominated as causal for type 2 diabetes with Mendelian randomization. Proteins unique to the longitudinal repeated analyses highlighted biological pathways (e.g., posttranslational protein modification and cellular structure and cycle regulation) that were distinct from pathways enriched among the shared proteins (e.g., small-molecule metabolic and catabolic processes). Longitudinal protein measurements identify additional novel disease biomarkers and disparate biological pathways compared with single measurement analyses.

Journal Article↗

PubMed2026

Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV.

People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1β, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4+ T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.

HIV↗