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Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Research output: Contribution to journalArticle

  • the 23 and Me Research Team
  • eQTLGen Consortium
  • BIOS Consortium
Original languageEnglish
Pages (from-to)665-684
Number of pages20
JournalAmerican Journal of Human Genetics
Volume104
Issue number4
Early online date28 Mar 2019
DOIs
DateAccepted/In press - 20 Feb 2019
DateE-pub ahead of print - 28 Mar 2019
DatePublished (current) - 4 Apr 2019

Abstract

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h 2 g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h 2 g = 10.6%). The genetic correlation (r g ) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h 2 g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

    Research areas

  • age, allergy, asthma, genetic, genome, GWAS, heritability, onset, overlap, risk

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    Rights statement: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://doi.org/10.1016/j.ajhg.2019.02.022 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 2 MB, PDF document

    Licence: CC BY-NC-ND

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