Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Thorunn A. Olafsdottir, Fannar Theódórs, Kristbjörg Bjarnadóttir, Unnur Steina Björnsdóttir, Arna B. Agustsdottir, Ólafur Andri Stefánsson, Erna V. Ivarsdottir, Jon K. Sigurdsson, Stefania Benónísdóttir, Guðmundur I. Eyjólfsson, Davíð Gíslason, Þórarinn Gíslason, Steinunn Guðmundsdóttir, Arnaldur Gylfason, Bjarni V. Halldórsson, Gísli H. Halldórsson, Thorhildur Juliusdottir, Anna M. Kristinsdottir, Dóra Lúðvíksdóttir, Björn R. Lúdvíksson, Gísli Másson, Kristján Norland, Páll T. Önundarson, Ísleifur Ólafsson, Ólöf Sigurðardóttir, Lilja Stefánsdóttir, Garðar Sveinbjörnsson, Vinicius Tragante, Daníel F. Guðbjartsson, Guðmar Þorleifsson, Patrick Sulem, Unnur Þorsteinsdóttir, Gudmundur L. Norddahl, Ingileif Jónsdóttir, Kāri Stefánsson
Abstract
Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.