Shared and distinct genetic risk factors for childhood onset and adult onset asthma

PIVIDORI, MILTON; OBER, CAROLE; SCHOETTLER, NATHAN; IM, HAE KYUNG; NICOLAE, DAN L.

San Diego

Congreso; American Society of Human Genetics 2018 Meeting; 2018

Asthma is the most prevalent chronic respiratory disease worldwide. Childhood onset asthma and adult onset asthma are distinct diseases with respect to sex ratios, triggers of exacerbation, associated co-morbidities, and severity, and potentially also for genetic risk factors. However, it remains unknown as to whether asthma risk loci are associated with age of onset or contribute specifically to childhood onset or adult onset asthma. Our goal was to provide insights into the molecular mechanisms contributing to the different clinical manifestations of asthma that is diagnosed at different ages. Toward that goal, we first determined shared and distinct genetic risk loci for childhood and adult onset asthma to assess the effects of associated loci on the age of onset of asthma. Then we identified candidate genes that may be mediating the effects of associations at shared and age of onset specific asthma loci. Leveraging the data available in the U.K. Biobank, this study is the first GWAS of age of onset in asthma that includes both childhood (9,433 cases, onset prior to 12 years of age) and adult onset asthma (23,395 cases, onset after 25 years), which were compared against participants without an asthma diagnosis (323,376 controls). Individuals with COPD were excluded, and all disease status, age of onset asthma and gender were extracted from self reported questionnaires and hospital records. Stratifying by age of onset revealed 63 independent asthma loci: 17 specific to childhood onset, 3 specific to adult onset, 5 shared but with significantly larger effect sizes in the childhood onset GWAS, and 38 additional shared loci. Among the 63 loci were 32 not reported in previous GWAS. Using a gene-based test, PrediXcan, we identified 120 unique genes associated with asthma, including 33 at 6 childhood onset asthma loci, one gene at an adult onset locus, 76 genes at 19 shared loci, and 10 genes outside the loci identified in the GWASs. Our findings of more childhood onset asthma loci and larger effect sizes of risk alleles in the childhood onset cases are particularly striking given that there were nearly 2.5-times more adult onset than childhood onset cases in this study. Overall, our study indicates that genetic risk for adult onset asthma is largely a subset of risk loci for childhood onset asthma, but with overall smaller effect sizes.