Author:
Chang Diana,Hunkapiller Julie,Bhangale Tushar,Reeder Jens,Mukhyala Kiran,Tom Jennifer,Cowgill Amy,Vogel Jan,Forrest William F.,Khan Zia,Stockwell Amy,McCarthy Mark I.,Staton Tracy L.,Olsson Julie,Holweg Cecile T. J.,Cheung Dorothy S.,Chen Hubert,Brauer Matthew J.,Graham Robert R.,Behrens Timothy,Wilson Mark S.,Arron Joseph R.,Choy David F.,Yaspan Brian L.
Abstract
AbstractGenome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls. We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci. Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci.
Publisher
Springer Science and Business Media LLC
Cited by
6 articles.
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