A computational framework called DANDELION has identified genes that drive asthma among the many linked in large genetic studies.
The mediation-inspired statistical framework is able to reveal candidate genes that play a central role in disease and could be targeted for treatment, but which escape detection through conventional means.
At the same, the approach rules out genes that have simply been associated with particular diseases through large genetic studies.
In asthma, it was also able to uncover a previously unrecognized biological process that appeared to play a key role in driving the inflammatory condition.
“Current genetic approaches and large-scale studies often identify hundreds of DNA changes linked to disease risk but it can be difficult to determine which genes are actually causing the disease rather than simply being associated with it,” said researcher Zhonghua Liu, ScD, from the University of Chicago.
“DANDELION gives researchers a more effective way to pinpoint those genes and the biological pathways they control.”
The findings appear in Cell and the DANDELION software package and analysis code have been made freely available.
The computational framework identifies disease-driving genes missed through conventional approaches by integrating transregulatory signals with rare-variant burden tests.
By combining large amounts of genetic data with trans-gene regulatory information from tissues relevant to a particular disease, it can identify important genes that are not revealed through traditional approaches.
The research team, led by Isabella Salamone, PhD, also from the University of Chicago, applied the framework to asthma and combined the results with single-cell gene expression data from the Human Cell Atlas to reveal lung cell types in which the identified genes were most active.
CRISPR screens in epithelial and T cells revealed that most disease-proximal genes regulated key asthma-related cellular phenotypes. Disease-proximal genes SLC27A3 and SCD were uncovered as key regulators, the loss of which affected inflammation and airway remodeling in a mouse model of allergic asthma.
DANDELION also revealed protein palmitoylation as a previously unknown central disease-mediating process that was involved in asthma pathogenesis and lung inflammation.
“Our findings suggest DANDELION can reveal clinically meaningful disease mechanisms that other approaches miss,” said Liu. “We anticipate it will help researchers identify new therapeutic targets across many complex diseases.”
