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Researchers found significant differences in genes potentially linked to adult-onset asthma and childhood-onset asthma, with little overlap between the two.

Significant differences were discovered in the sets of genes potentially linked to adult-onset asthma (AOA) and childhood-onset asthma (COA), with relatively little overlap between the two, according to a recent study published online in Genome Medicine.

Combining experimental and computational approaches to reanalyze genome-wide association study (GWAS) data for both AOA and COA, the researchers uncovered hundreds of genetic variants with a high likelihood of having a causal effect on both types of asthma.

“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 co-senior author Carole Ober, PhD, chair of the University of Chicago Department of Human Genetics. “You find out it’s actually different variants that are contributing to asthma. Even when the GWAS locus looks the same, the genes functionally linked to these variants are also different. So, they’re really quite different diseases.”

Distinct Molecular Signatures

To estimate the probability that a given genetic variant has a causal relationship with asthma, the team applied fine-mapping—a statistical technique—to GWAS summary statistics from the UK Biobank.

“The GWAS associations provide sets of variants associated with the disease,” explained first author Xiaoyuan (Ethan) Zhong, a University of Chicago PhD student. “So, when those variants overlap with open chromatin regions in cell types that are relevant to asthma pathogenesis like lung epithelial cells, we think that they are more likely to be causal to these asthma phenotypes.” 

Next, the researchers incorporated data on expression quantitative trait loci, genetic variants associated with differences in gene expression, and chromatin interactions from blood and lung cell types to link fine-mapped variants to their target genes, further refining their list of likely causal genes.

Fine-Mapping & Functional Validation

Fine-mapping analysis revealed 21 credible sets of variants for AOA and 67 for COA, with just 16% of sets shared by the two. The investigators then searched these loci for cis-regulatory elements linked to asthma. They nominated 62 candidate genes for AOA and 169 for COA, more than 60% of which exhibited open chromatin in multiple cell lineages, including many genes involved in immune and inflammatory responses.

Finally, to confirm regulatory effect, six of these candidate elements were tested in bronchial epithelial cells using luciferase reporter assays. According to the study, four showed allele-specific activity consistent with the asthma-risk variant, narrowing the variant-to-function gap.

Valuable Resource for the Future

Although constrained by its focus on open chromatin annotations and a predominantly European cohort, the study lays the groundwork for precision medicine strategies that distinguish AOA and COA at the molecular level.

“Our datasets provide a valuable resource for future functional studies to understand the biological mechanisms underlying the genetics of asthma with onset in both childhood and later in life,” the authors concluded.