Genome-wide association studies (GWAS) have identified hundreds of genomic regions associated with asthma. However, pinpointing which of these genetic variants actually cause the disease has remained a major challenge. This “variant-to-function” gap has hindered the practical application of GWAS findings for treatment development.
Now, a new study from the University of Chicago has taken a significant step forward. By integrating advanced computational tools with large-scale genetic data, researchers have identified numerous genetic variants with a high likelihood of directly contributing to either childhood- or adult-onset asthma. Their findings, published in Genome Medicine, could pave the way for more targeted therapies based on the distinct genetic makeup of each asthma subtype.
Childhood vs. Adult-Onset Asthma: Genetically Distinct Diseases
The study found remarkably little genetic overlap between childhood-onset and adult-onset asthma. While previous GWAS suggested shared loci, this new analysis revealed that different variants—and even different genes within the same locus—are functionally relevant depending on the age of onset.
“The real uniqueness of our study is that the differences between childhood- and adult-onset asthma were evident at every level that we looked at,” said Carole Ober, PhD, the Blum-Riese Distinguished Service Professor and Chair of Human Genetics at UChicago. “So, they’re really quite different diseases.”
Fine-Mapping Causal Variants: A Closer Look
Traditional GWAS detect statistical associations between genetic variants and disease risk. However, most of these variants lie in non-coding regions of the genome and are inherited in blocks, making it difficult to determine which are actually causative.
To overcome this, Ethan Zhong, a graduate student at UChicago, applied a fine-mapping technique to genetic data from the UK Biobank, which contains DNA and health information from nearly 500,000 individuals. This method estimates the probability that any given variant within a genomic region is causally linked to asthma.
The researchers added another layer of analysis by incorporating chromatin accessibility data. Chromatin, the complex of DNA and proteins that forms chromosomes, becomes more “open” in regions involved in gene regulation. When asthma-associated variants overlapped with these open chromatin regions in relevant cells—such as lung epithelial cells—it strengthened the case for their causal role.
Linking Variants to Function
Zhong didn’t stop at identifying likely causal variants. He also examined expression quantitative trait loci (eQTLs)—variants that influence gene expression—and chromatin interaction data from lung and blood cells. This allowed him to link specific variants to the genes they regulate, resulting in a list of high-confidence candidate genes.
“When those variants overlap with open chromatin regions in cell types relevant to asthma pathogenesis, we think that they are more likely to be causal to these asthma phenotypes,” said Zhong.
Key Findings: Different Genes, Different Paths
The analysis identified 21 credible variant sets for adult-onset asthma and 67 for childhood-onset asthma, with just 16% shared between them. The team also pinpointed cis-regulatory elements (CREs)—short DNA sequences that control nearby gene expression—connected to 62 genes in adult-onset asthma and 169 in childhood-onset asthma.
More than 60% of these candidate genes showed open chromatin in immune and inflammatory cell types, supporting their biological relevance.
To validate their approach, the team tested six of these CREs in bronchial epithelial cells. Four of the six showed regulatory activity, confirming that they influence gene expression in relevant tissues.
Bridging the Variant-to-Function Gap
This study demonstrates the power of combining fine-mapping techniques with functional genomic data to clarify the biological mechanisms underlying complex diseases like asthma. By identifying genes and regulatory elements linked to asthma risk, researchers are moving closer to developing precise interventions tailored to the genetic profile of different patient groups.
“Our findings highlight the need to consider childhood- and adult-onset asthma as distinct conditions,” said co-senior author Xin He, PhD, Associate Professor of Human Genetics. “Understanding their genetic architecture is essential to uncovering new therapeutic targets.”
Research Support and Collaborators
This research was supported in part by a National Institutes of Health (NIH) grant focused on asthma and allergy gene discovery. Collaborators included Marcelo Nobrega, MD, PhD; Nathan Schoettler, MD, PhD; and Anne Sperling, PhD, now at the University of Virginia.
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