Academic Journal
Causal modelling of gene effects from regulators to programs to traits.
| Τίτλος: | Causal modelling of gene effects from regulators to programs to traits. |
|---|---|
| Συγγραφείς: | Ota M; Department of Genetics, Stanford University, Stanford, CA, USA. mineto-ota@g.ecc.u-tokyo.ac.jp.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. mineto-ota@g.ecc.u-tokyo.ac.jp.; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. mineto-ota@g.ecc.u-tokyo.ac.jp., Spence JP; Department of Genetics, Stanford University, Stanford, CA, USA.; Institute for Human Genetics (IHG), University of California San Francisco, San Francisco, CA, USA.; Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA., Zeng T; Department of Genetics, Stanford University, Stanford, CA, USA., Dann E; Department of Genetics, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., Milind N; Department of Genetics, Stanford University, Stanford, CA, USA., Marson A; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. alex.marson@gladstone.ucsf.edu.; Institute for Human Genetics (IHG), University of California San Francisco, San Francisco, CA, USA. alex.marson@gladstone.ucsf.edu.; Department of Medicine, University of California San Francisco, San Francisco, CA, USA. alex.marson@gladstone.ucsf.edu.; UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. alex.marson@gladstone.ucsf.edu.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. alex.marson@gladstone.ucsf.edu.; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. alex.marson@gladstone.ucsf.edu.; Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, USA. alex.marson@gladstone.ucsf.edu., Pritchard JK; Department of Genetics, Stanford University, Stanford, CA, USA. pritch@stanford.edu.; Department of Biology, Stanford University, Stanford, CA, USA. pritch@stanford.edu. |
| Πηγή: | Nature [Nature] 2026 Feb; Vol. 650 (8101), pp. 399-408. Date of Electronic Publication: 2025 Dec 10. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| Ιατρικοί όροι (MeSH): | Causality* , Gene Expression Regulation* , Genetic Association Studies* , Models, Genetic*, Humans ; Gene Regulatory Networks ; Genome-Wide Association Study ; Loss of Function Mutation ; Phenotype ; Quantitative Trait Loci ; Quantitative Trait, Heritable ; Animals |
| Περίληψη: | Genetic association studies provide a unique tool for identifying candidate causal links from genes to human traits and diseases. However, it is challenging to determine the biological mechanisms underlying most associations, and we lack genome-scale approaches for inferring causal mechanistic pathways from genes to cellular functions to traits. Here we propose approaches to bridge this gap by combining quantitative estimates of gene-trait relationships from loss-of-function burden tests1 with gene-regulatory connections inferred from Perturb-seq experiments2 in relevant cell types. By combining these two forms of data, we aim to build causal graphs in which the directional associations of genes with a trait can be explained by their regulatory effects on biological programs or direct effects on the trait3. As a proof of concept, we constructed a causal graph of the gene-regulatory hierarchy that jointly controls three partially co-regulated blood traits. We propose that perturbation studies in trait-relevant cell types, coupled with gene-level effect sizes for traits, can bridge the gap between genetic association and biological mechanism. (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: A.M. is a cofounder of Site Tx, Arsenal Biosciences and Survey Genomics; serves on the boards of directors at Site Tx and Survey Genomics; is a member of the scientific advisory boards of network.bio, Site Tx, Arsenal Biosciences, Cellanome, Survey Genomics, NewLimit, Amgen and Tenaya; owns stock in network.bio, Arsenal Biosciences, Site Tx, Cellanome, NewLimit, Survey Genomics, Tenaya and Lightcast; has received fees from network.bio, Site Tx, Arsenal Biosciences, Cellanome, Spotlight Therapeutics, NewLimit, AbbVie, Gilead, Pfizer, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Lightcast, Trizell, Vertex, Merck, Amgen, Genentech, GLG, ClearView Healthcare, AlphaSights, Rupert Case Management, Bernstein and ALDA; is an investor in and informal advisor to Offline Ventures; and is a client of EPIQ. The Marson laboratory has received research support from the Parker Institute for Cancer Immunotherapy, the Emerson Collective, Arc Institute, Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead and Anthem and reagents from Genscript, Illumina and Cellanome. The remaining authors declare no competing interests. |
| Σχόλια: | Update of: bioRxiv. 2025 Jan 24:2025.01.22.634424. doi: 10.1101/2025.01.22.634424.. (PMID: 39896538) |
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| Grant Information: | R01 HG008140 United States HG NHGRI NIH HHS; R01 HG011432 United States HG NHGRI NIH HHS; R01 HG014005 United States HG NHGRI NIH HHS; U01 HG012069 United States HG NHGRI NIH HHS |
| Entry Date(s): | Date Created: 20251210 Date Completed: 20260212 Latest Revision: 20260920 |
| Update Code: | 20260920 |
| PubMed Central ID: | PMC12893915 |
| DOI: | 10.1038/s41586-025-09866-3 |
| PMID: | 41372418 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1476-4687 |
|---|---|
| DOI: | 10.1038/s41586-025-09866-3 |