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Shared and distinct genetic risk factors for childhood onset and adult onset asthma: genome- and transcriptome-wide Studies

By Milton Pividori, Nathan Schoettler, Dan L Nicolae, Carole Ober, Hae Kyung Im

Posted 26 Sep 2018
bioRxiv DOI: 10.1101/427427 (published DOI: 10.1016/S2213-2600(19)30055-4)

Childhood and adult onset asthma differ with respect to severity and co-morbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood and adult onset asthma, and the genes that may mediate the effects of associated variation. We used data from UK Biobank to conduct genome-wide association studies (GWASs) in 37,846 subjects with asthma, including 9,433 childhood onset cases (onset before age 12) and 21,564 adult onset cases (onset between ages 26 and 65), and 318,237 subjects without asthma (controls; older than age 38). We conducted GWASs for childhood onset asthma and adult onset asthma each compared to shared controls, and for age of asthma onset in all 37,846 asthma cases. 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. 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. Genes at the childhood onset loci were most highly expressed in skin, blood and small intestine; genes at the adult onset 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. 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. In contrast, the onset of disease in childhood is associated with additional genes with relatively large effect sizes, and SNP-based heritability estimates that are over 3-times larger than for adult onset disease. 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 etiology of adult onset asthma is more lung-centered and environmentally determined, but with immune mediated mechanisms driving disease progression in both children and adults.

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