A recent study by researchers from the University of Chicago has made significant strides in understanding the genetic causes of asthma. While genome-wide association studies (GWAS) have identified hundreds of genetic variants linked to asthma, determining which of these variants have a direct causal relationship with the disease has remained a significant challenge. The study, published in Genome Medicine, aims to bridge this “variant-to-function” gap by combining genetic data with advanced computational tools to identify causal variants in both adult-onset and childhood-onset asthma.
Understanding the Variant-to-Function Gap
GWAS has revealed numerous genetic variants associated with asthma by comparing the genome sequences of individuals with the disease to those without it. However, most human diseases, including asthma, are not caused by a single genetic variant. They result from complex interactions between multiple genes, environmental factors, and other variables. As a result, GWAS often produces an overwhelming number of potential variants, which need further refinement to be useful for understanding disease mechanisms.
Moreover, GWAS only reveals associations between genetic variants and disease but does not confirm causality. A major complication arises because most genetic variants tied to diseases are found in non-coding regions of the genome, making it difficult to determine their functional significance.
The University of Chicago team, led by Carole Ober, PhD, and Xin He, PhD, sought to close this gap by utilizing fine-mapping techniques. Fine-mapping aims to estimate the probability that a particular genetic variant is directly responsible for the disease. This approach provides a more focused and refined understanding of the genetic components of asthma.
Fine-Mapping and Computational Tools
Ethan Zhong, a graduate student working with Ober and He, used data from the UK Biobank, a large biomedical resource that contains genetic data from nearly 500,000 individuals in the UK. By applying fine-mapping to GWAS data, Zhong identified variants with a higher likelihood of being causally related to asthma. This approach incorporated data on chromatin accessibility, which indicates whether a region of the genome is active in regulating gene expression. When chromatin opens, it is more likely to regulate nearby genes, providing additional support for the hypothesis that certain variants are involved in the disease.
Zhong also integrated data on expression quantitative trait loci (eQTLs), which link genetic variants to differences in gene expression, and chromatin interactions from various cell types, including blood and lung cells. By combining these data, the research team was able to refine their understanding of which genetic variants are more likely to play a causal role in asthma.
Key Findings: Childhood vs. Adult-Onset Asthma
The study revealed that childhood-onset and adult-onset asthma are genetically distinct conditions, with very few overlapping variants. Zhong’s fine-mapping analysis uncovered 21 independent sets of variants associated with adult-onset asthma and 67 sets associated with childhood-onset asthma. Only 16% of the variants were shared between the two forms of asthma, indicating significant genetic differences between them.
In addition, the study identified 62 candidate genes for adult-onset asthma and 169 for childhood-onset asthma. These genes are involved in immune and inflammatory responses, processes that are crucial to the development of asthma. Many of these genes also showed open chromatin in relevant cell types, such as lung epithelial cells, further supporting their potential role in asthma.
Testing Causal Variants
To confirm that some of the candidate variants were indeed functional, the researchers selected six candidate cis-regulatory elements (CREs) for further testing. CREs are short DNA sequences that regulate the expression of nearby genes. When tested in bronchial epithelial cells, four of the six CREs showed a regulatory effect, providing additional evidence that these variants play a role in asthma.
Implications for Future Research and Treatment
This study represents a significant step toward closing the variant-to-function gap in asthma genetics. By fine-mapping GWAS results and identifying candidate genes involved in immune responses, the researchers have laid the groundwork for future studies targeting these genes as potential treatments for asthma.
The findings underscore the importance of continued genetic research into asthma, with an emphasis on understanding the distinct genetic causes of childhood-onset and adult-onset forms of the disease. With further refinement of these genetic insights, researchers hope to develop targeted therapies that could address the root causes of asthma, offering new hope for patients with this chronic respiratory condition.
Overall, this research not only enhances our understanding of the genetic basis of asthma but also paves the way for more personalized treatment approaches that could improve outcomes for individuals suffering from both childhood and adult-onset asthma.
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