Researchers report that a genome-wide association study (GWAS) demonstrated that childhood-onset asthma was associated with nearly three times as many genes as adult-onset asthma. Genes associated with adult-onset asthma were a subset of those associated with childhood-onset asthma, nearly all with smaller effects on adult-onset asthma than on childhood-onset asthma.
The team’s work (“Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies”) appears in Lancet Respiratory Medicine.
“We did genome-wide and transcriptome-wide studies, using data from the UK Biobank, in individuals with asthma, including adults with childhood-onset asthma (onset before 12 years of age), adults with adult-onset asthma (onset between 26 and 65 years of age), and adults without asthma (controls; aged older than 38 years). We did genome-wide association studies (GWAS) for childhood-onset asthma and adult-onset asthma each compared with shared controls, and for age of asthma onset in all asthma cases, with a genome-wide significance threshold of p<5 × 10−8. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.
“Of 376,358 British white individuals from the UK Biobank, we included 37,846 with self-reports of doctor-diagnosed asthma: 9,433 adults with childhood-onset asthma; 21,564 adults with adult-onset asthma; and an additional 6,849 young adults with asthma with onset between 12 and 25 years of age. For the first and second GWAS analyses, 318,237 individuals older than 38 years without asthma were used as controls. We detected 61 independent asthma loci: 23 were childhood-onset specific, one was adult-onset specific, and 37 were shared. Nineteen loci were associated with age of asthma onset. The most significant asthma-associated locus was at 17q12 (odds ratio 1·406, 95% CI 1·365–1·448; p=1·45 × 10−111) in the childhood-onset GWAS. Genes at the childhood onset-specific loci were most highly expressed in skin, blood, and small intestine; genes at the adult onset-specific loci were most highly expressed in lung, blood, small intestine, and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci. Single-nucleotide polymorphism-based heritability estimates were more than three times larger for childhood-onset asthma (0·327) than for adult-onset disease (0·098). The onset of disease in childhood was associated with additional genes with relatively large effect sizes, with the largest odds ratio observed at the FLG locus at 1q21.3 (1·970, 95% CI 1·823–2·129).
“Genetic risk factors for adult-onset asthma are largely a subset of the genetic risk for childhood-onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult-onset asthma. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes, whereas the cause of adult-onset asthma is more lung-centered and environmentally determined, but with immune-mediated mechanisms driving disease progression in both children and adults.”
“This was the largest asthma-related GWAS yet attempted,” said study co-author Carole Ober, PhD, professor and chair of the department of human genetics at the University of Chicago, and her collaborator Hae Kyung Im, PhD, assistant professor in the department of medicine. “We found that the genes involved in adult-onset asthma are largely a subset of genes associated with childhood asthma. At later ages, however, the same genes tend to have smaller effects.”
The authors add that both the “childhood-specific and shared loci were associated with the development of asthma at younger ages and those alleles all had larger effects in childhood-onset compared to adult-onset asthma.”