Researchers from University of Chicago and Columbia University developed DANDELION, a computational tool that identified 21 disease-proximal genes directly driving asthma development, revealing protein palmitoylation as a previously unknown biological pathway that could become a new therapeutic target for asthma treatment.
- DANDELION tool identifies disease-proximal genes that directly influence asthma, moving beyond traditional genome-wide association studies that only catalog associated variants
- Researchers discovered 21 asthma-related genes, most previously unrecognized, with over 70% significantly affecting epithelial barrier integrity in airway cells
- Two key genes—SLC27A3 and SCD—regulate protein palmitoylation, a post-translational modification that appears central to asthma development
A team of researchers from University of Chicago and Columbia University has developed a powerful genetic analysis tool that may transform how scientists identify the genes most responsible for complex diseases such as asthma. Using the computational framework, DANDELION, investigators discovered previously unrecognized asthma-driving genes and identified a surprising biological pathway involving protein palmitoylation that could become a future therapeutic target. The discovery was outlined in the paper, “Trans-Regulatory Gene Mapping Prioritizes Disease Drivers in Asthma,” and published in Cell.
For years, genome-wide association studies (GWAS) have uncovered thousands of genetic variants linked to disease, investigators said. However, researchers have struggled to determine which genes are true disease drivers and which ones indirectly influence disease.
To address this challenge, the researchers created DANDELION, a tool designed to identify what they call disease-proximal genes (DPGs). These genes sit at key points within gene-regulatory networks and are believed to directly influence disease development, they said. DANDELION combines trans-regulatory gene interactions with whole-exome sequencing data to pinpoint these critical genes.
According to the researchers, most disease-associated genetic variants likely exert their effects through a relatively small set of these central genes. By identifying them, scientists may gain a clearer picture of disease biology and uncover more effective drug targets.
The team applied DANDELION to asthma. Researchers noted that although previous studies have identified nearly 200 asthma-associated genetic regions, many of the underlying biological mechanisms remain poorly understood.
Using data from the United Kingdom Biobank and large-scale gene regulation datasets, DANDELION identified 21 asthma-related DPGs, most of which had not been highlighted by traditional genetic approaches. Only a small number overlapped with known asthma risk genes. The study’s authors suggested the method can uncover previously hidden contributors to the disease.
Researchers found that many of these genes were involved in endoplasmic reticulum function and cellular stress responses, processes already suspected to play a role in airway inflammation.
To test whether the newly identified genes truly influence asthma, investigators performed extensive CRISPR gene-editing experiments in airway epithelial cells and immune T cells.
The results were striking. More than 70% of the prioritized asthma genes significantly affected epithelial barrier integrity, a crucial function that is often impaired in asthma patients. Several of the genes also regulated production of IL-13, a key inflammatory molecule involved in allergic asthma.
Researchers reported that disease-proximal genes consistently had stronger effects on asthma-related cellular functions than genes identified through conventional GWAS methods alone.
Among the most important discoveries were two genes: SLC27A3 and SCD.
SLC27A3 helps transport long-chain fatty acids into cells and contributes to production of molecules involved in inflammation, researchers said. When they disabled the gene, they observed reduced inflammatory signaling, improved epithelial barrier function and lower IL-13 production — all changes associated with protection from asthma.
The second gene, SCD, operates in the same metabolic pathway but produces opposite effects, the authors noted. Loss of SCD increased asthma-like characteristics in both cellular and animal experiments.
Together, researchers said the findings pointed to a previously underappreciated process called protein palmitoylation, a post-translational modification that affects protein signaling and cellular communication. The study suggests that dysregulation of palmitoylation may be a central mechanism driving asthma development.
To determine whether the discoveries could translate beyond laboratory cells, researchers tested the findings in a mouse model of allergic asthma. Mice lacking the SLC27A3 gene displayed significantly reduced airway inflammation, fewer eosinophils, less mucus production and decreased airway remodeling after allergen exposure. By contrast, mice lacking SCD1 (the mouse equivalent of SCD) experienced more severe inflammation.
The researchers said they believe DANDELION could be applied far beyond asthma, helping scientists identify disease-driving genes across a wide range of complex conditions.
By focusing on disease-proximal genes rather than simply cataloging associated genetic variants, they said, the framework may improve the success rate of therapeutic target discovery. The study also highlights protein palmitoylation as a promising new area for asthma drug development, potentially offering alternatives to current anti-inflammatory treatments, the authors noted.
