124: Omnigenic Architecture and Core Genes in Ulcerative Colitis

Ratajczak F et al., The American Journal of Human Genetics - This study uses the Speos graph machine-learning framework on multi-modal molecular networks to identify core genes for complex traits, focusing on ulcerative colitis (UC). It shows tissue-specific core-gene expression, coordinated regulation of core genes after perturbation, and frequent non-linear interactions in co-perturbations. Key terms: omnigenic, core genes, ulcerative colitis, Speos, perturbation. Study Highlights:Using Speos, the authors identify confident core-gene sets for UC that are enriched for tissue-specific expression and disease-relevant network connections. Genome-scale perturbation data show that about one-third of knockdown or overexpression perturbations differentially affect core versus peripheral genes, a pattern not seen for GWAS or random gene sets. Core genes respond in a concerted manner across traits and cell lines, while co-perturbation simulations predict frequent non-linear genetic interactions between core genes. These results extend the omnigenic model by highlighting coordinated regulation and interaction among core genes as mechanisms that can contribute to heritability. Conclusion:Core genes occupy central, tissue-relevant positions in molecular networks and are coherently regulated by perturbations across the genome; non-additive interactions among core genes add a further layer of complexity to the omnigenic model and to how peripheral variation may influence disease. Music:Enjoy the music based on this article at the end of the episode. Article title:Exploring the omnigenic architecture of selected complex traits First author:Ratajczak F Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2025.07.006 Reference:Ratajczak F., Heinig M., Falter-Braun P. (2025). Exploring the omnigenic architecture of selected complex traits. The American Journal of Human Genetics 112, 1–23. https://doi.org/10.1016/j.ajhg.2025.07.006 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/exploring-the-omnigenic-architecture-of-selected-complex-traits QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-01. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing the omnigenic model, core vs peripheral genes, Speos multi-modal network, 72-tissue expression features, LINCS perturbation analyses, GEARS co-perturbations, cross-disease validation (CAD and SCZ), mouse knockout and human tissue expression evidence, and clinical implications for- transcript topics: Omnigenic model overview with core vs peripheral genes; Speos: multi-modal network construction and core-gene identification; Immune-tissue expression of UC core genes versus colon; LINCS perturbation analyses showing concerted core gene regulation; GEARS co-perturbation simulations: non-additive interactions (neomorphism, suppression); Cross-trait validation: CAD and schizophrenia architectures QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi...