A recent investigation conducted by scientists at the University of Chicago has brought significant advancements in understanding the genetic underpinnings of asthma. By merging genetic data with refined computational methodologies, researchers have identified numerous genetic variants that likely play a causal role in both adult-onset and childhood-onset asthma. This breakthrough paves the way for targeted gene studies aimed at developing potential treatments. The study also highlights substantial differences between the genetic factors linked to each type of asthma.
The complexity of genome-wide association studies (GWAS) lies in distinguishing truly causal genetic variants from those merely associated with the disease. Using an advanced technique known as "fine-mapping," researchers estimated the probability of specific variants causing asthma. They integrated chromatin accessibility data and expression quantitative trait loci (eQTLs) to strengthen their findings, identifying distinct sets of variants for each asthma type.
Refining Genetic Insights Through Computational Techniques
Researchers employed innovative statistical methods to delve deeper into GWAS results for asthma. These methods enabled them to estimate the likelihood of certain genetic variants being causally linked to the disease. By integrating chromatin accessibility data, they strengthened the evidence supporting these causal links, focusing on cell types relevant to asthma development.
Traditionally, GWAS identifies numerous genetic variants associated with diseases like asthma, but discerning which ones are truly causal remains challenging. In this study, Ethan Zhong utilized the UK Biobank's extensive dataset to apply fine-mapping techniques. This approach estimates the probability that a given variant is causally related to asthma. By analyzing chromatin accessibility in lung epithelial cells and other relevant cell types, Zhong pinpointed variants more likely to influence asthma phenotypes. Additionally, incorporating eQTL data and chromatin interaction information allowed him to connect these variants to their target genes, thereby building a robust list of likely causal genes supported by genetic evidence.
Distinct Genetic Profiles for Adult-Onset and Childhood-Onset Asthma
The analysis uncovered marked distinctions in genetic profiles between adult-onset and childhood-onset asthma. Independent sets of variants were identified for each type, with minimal overlap. This finding underscores the unique genetic mechanisms underlying each form of the disease. Furthermore, candidate genes linked to regulatory elements provided additional insights into the biological pathways involved in asthma.
The fine-mapping process revealed 21 independent variant sets for adult-onset asthma and 67 for childhood-onset, sharing only 16% similarity. Researchers also identified cis-regulatory elements (CREs) connected to asthma, uncovering 62 and 169 candidate genes for adult-onset and childhood-onset asthma, respectively. A significant portion of these genes exhibited open chromatin in various cell types, many of which are implicated in immune and inflammatory responses. To validate their findings, the team tested six candidate CREs in bronchial epithelial cells, confirming regulatory effects in four out of six cases. This success demonstrates progress in narrowing the gap between genetic variants and their functional implications, setting the stage for further exploration of these genes as potential therapeutic targets.