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Trans-regulatory gene mapping prioritizes disease drivers in asthma
Isabella M Salamone1, Peixin Tian2, Zining Qi3
1Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Cell
|August 11, 2026
Summary
Identifying key disease-driving genes is crucial. Our new DANDELION framework prioritizes disease-proximal genes (DPGs) by integrating genetic and tissue data, revealing novel asthma targets.
Area of Science:
- Human Genetics
- Systems Biology
- Immunology
Background:
- Identifying causative genes for diseases remains a significant challenge in human genetics.
- Genome-wide association studies (GWAS) identify many variants, but most likely indirectly regulate a core set of disease-driving genes.
- These central genes, termed disease-proximal genes (DPGs), are largely unidentified.
Purpose of the Study:
- To introduce DANDELION, a novel statistical framework for prioritizing DPGs.
- To integrate trans-regulatory effects from relevant tissues with whole-exome sequencing data.
- To identify novel, therapeutically relevant genes in complex diseases like asthma.
Main Methods:
- Developed DANDELION, a mediation-inspired statistical framework.
- Integrated gene expression data from disease-relevant tissues with whole-exome sequencing.
- Utilized CRISPR screens in relevant cell types (epithelial, T cells).
- Validated findings in a mouse model of allergic asthma.
Main Results:
- DANDELION successfully identified novel DPGs for asthma that are missed by conventional methods.
- CRISPR screens confirmed that identified DPGs regulate key asthma-related cellular phenotypes.
- Functional studies in mice showed that loss of SLC27A3 and SCD impacts asthma inflammation and airway remodeling.
Conclusions:
- DANDELION is a powerful new framework for prioritizing disease-proximal genes.
- The identified DPGs represent novel, potentially therapeutic targets for asthma.
- This approach advances the understanding of disease pathogenesis and gene function.
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