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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)

Background 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. Methods 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. Findings 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. Interpretation 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. Funding This work was supported by the National Institutes of Health grants R01 MH107666 and P30 DK20595 to HKI, R01 HL129735, R01 HL122712, P01 HL070831, and UG3 OD023282 to CO; NS was supported by T32 HL007605. Evidence before this study Genome-wide association studies in large samples that include both childhood onset and adult onset asthma have identified many loci associated with asthma risk. However, little was known about the shared or distinct effects of those or other loci on age of asthma onset, or about the genes that may mediate the effects of loci associated with childhoon and/or adult onset asthma. Added value of this study Leveraging the resources of UK Biobank, we identified loci with both age of onset specific effects and shared effects. We further showed a significantly greater contribution of genetic variation to childhood onset asthma, implying a greater role for environmental risk factors in adult onset asthma, and different biological pathways and tissue enrichments for genes at loci associated with childhood vs adult onset asthma. Implications of all the available evidence Our results suggest that childhood onset specific loci and those associated with age of onset play a role in disease initiation, whereas the other associated loci reflect shared mechanisms of disease progression. The childhood onset specific loci highlight skin as a primiary target tissue for early onset disease and support the idea that asthma in childhood is due to impaired barrier function in the skin and other epithelial surfaces.

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