Genetic differences according to onset age and lung function in asthma: A cluster analysis

The extent of differences between genetic risks associated with various asthma subtypes is still unknown. To better understand the heterogeneity of asthma, we employed an unsupervised method to identify genetic variants specifically associated with asthma subtypes. Our goal was to gain insight into the genetic basis of asthma.

In this study, we utilized the UK Biobank dataset to select asthma patients (All asthma, n = 50,517) and controls (n = 283,410). We excluded 14,431 individuals who had no information on predicted values of forced expiratory volume in one second percent (FEV1%) and onset age, resulting in a final total of 36,086 asthma cases. We conducted k-means clustering based on asthma onset age and predicted FEV1% using these samples (n = 36,086). Cluster-specific genome-wide association studies were then performed, and heritability was estimated via linkage disequilibrium score regression. To further investigate the pathophysiology, we conducted eQTL analysis with GTEx and gene-set enrichment analysis with FUMA.

Clustering resulted in four distinct clusters: early onset asthma^normalLF (early onset with normal lung function, n = 8172), early onset asthma^reducedLF (early onset with reduced lung function, n = 8925), late-onset asthma^normalLF (late-onset with normal lung function, n = 12,481), and late-onset asthma^reducedLF (late-onset with reduced lung function, n = 6508). Our GWASs in four clusters and in All asthma sample identified 5 novel loci, 14 novel signals, and 51 cluster-specific signals. Among clusters, early onset asthma^normalLF and late-onset asthma^reducedLF were the least correlated (r_g  = 0.37). Early onset asthma^reducedLF showed the highest heritability explained by common variants (h²  = 0.212) and was associated with the largest number of variants (71 single nucleotide polymorphisms). Further, the pathway analysis conducted through eQTL and gene-set enrichment analysis showed that the worsening of symptoms in early onset asthma correlated with lymphocyte activation, pathogen recognition, cytokine receptor activation, and lymphocyte differentiation.

Our findings suggest that early onset asthma^reducedLF was the most genetically predisposed cluster, and that asthma clusters with reduced lung function were genetically distinct from clusters with normal lung function. Our study revealed the genetic variation between clusters that were segmented based on onset age and lung function, providing an important clue for the genetic mechanism of asthma heterogeneity.