This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance and linking IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.
Abstract
Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.
Migraine is a leading cause of disability, yet preventive treatment remains largely empirical despite the availability of several mechanistically distinct therapies. Genetic data can clarify mechanisms and therapeutic hypotheses when association signals are integrated with molecular and clinical data. We meta-analyzed migraine GWAS data from 12 European ancestry cohorts (206,893 cases and 2,093,175 controls) and four African ancestry cohorts (22,115 cases and 178,626 controls). We identified 311 lead variants in European-ancestry analyses and 316 lead variants in trans-ancestry analysis. Fine-mapping and transcriptome-wide analyses prioritized variants and genes implicated in sensory neuronal signaling, vascular tone, and immune regulation, with convergent evidence at several established loci including TRPM8 and PHACTR1. Drug-repurposing analyses identified therapeutic targets and compounds, including established migraine treatments and candidates requiring experimental validation. Genetic correlations, Mendelian randomization, and a phenome-wide scan linked migraine liability to psychiatric, pain, and gastrointestinal phenotypes. Together, these findings expand the known genetic architecture of migraine across ancestries and provide a genetics-led map connecting association signals with biological pathways, multimorbidity and candidate therapeutic mechanisms, providing a foundation for future functional and translational studies.
C. Overstreet, M. Galimberti, K. Harsan et al.· medRxiv· 0 citations
New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
J. Leite, G. F. L. Pascoal, G. B. S. Duarte et al.· Frontiers in Immunology· 0 citations
Metabolic syndrome (MetS), characterized by a cluster of interrelated metabolic abnormalities including central obesity, elevated blood pressure, dysglycemia, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol (HDL-C), substantially increases type 2 diabetes and cardiovascular disease risk. Conventional genome-wide association studies (GWASs) analyze individual traits or a dichotomized MetS status, only partially capturing its heritability and potentially overlooking variants with shared (pleiotropic) effects across correlated traits. Here, we performed a multiple-trait GWAS using data from the Korean Genome and Epidemiology Study. Using the Korea Biobank Array (K-Chip), we analyzed a discovery cohort from the Ansan and Ansung studies (1490 cases and 3856 controls) and validated the findings in CAVAS (3620 cases and 4461 controls) and HEXA (15,257 cases and 41,807 controls) cohorts. We jointly modeled six MetS-related traits using the complementary multivariate frameworks Multiple Phenotype Association Tests and Genome-wide Efficient Mixed Model Association, alongside a baseline logistic regression. Whereas logistic regression detected 2 APOA5 variants (rs662799 and rs2075291), the multivariate analyses identified 79 significant single-nucleotide polymorphisms; all were replicated in the HEXA cohort. Functional annotation prioritized 27 high-risk variants mapping to 12 genes, whereas pathway analysis (DAVID) implicated eight Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways related to lipid metabolism. Our findings demonstrate that multivariate analysis substantially improves the identification of pleiotropic susceptibility loci for MetS in the Korean population and indicates candidate genes for early detection and management.
Dasom Kim, Jun-Ho Cha, Sungkyoung Choi· International Journal of Mol...· 0 citations
This study indicates a genetic correlation and common risk genes, linking adiposity-related traits to PE-related diseases, and offers novel insights into the biological mechanisms underlying this comorbidity.
Yuping Shan, Hong Hu, Chong Liu et al.· Journal of Obstetrics and Gy...· 0 citations
An atlas of brain IDPs associated with bipolar disorder is established, by integrating epidemiological and genetic evidence, and candidate IDPs that were consistently associated with BD are highlighted across complementary analyses.
Wenzhuo Yang, Lin Pan, Haoqun Xie et al.· BMC Medicine· 0 citations
These findings implicate lipid metabolism, body weight regulation, and central nervous system mechanisms in antipsychotic-associated metabolic changes and may inform future precision medicine approaches to risk prediction and treatment selection.
H. Kazemi, J. E. Drake, S. Bacanu et al.· medRxiv· 0 citations
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