Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

Thorunn A. Olafsdottir, Fannar Theodors, Kristbjorg Bjarnadottir, Unnur Steina Bjornsdottir, Arna B. Agustsdottir, Olafur A. Stefansson, Erna V. Ivarsdottir, Jon K. Sigurdsson, Stefania Benonisdottir, Gudmundur I. Eyjolfsson, David Gislason, Thorarinn Gislason, Steinunn Guðmundsdóttir, Arnaldur Gylfason, Bjarni V. Halldorsson, Gisli H. Halldorsson, Thorhildur Juliusdottir, Anna M. Kristinsdottir, Dora Ludviksdottir, Bjorn R. Ludviksson, Gisli Masson, Kristjan Norland, Pall T. Onundarson, Isleifur Olafsson, Olof Sigurdardottir, Lilja Stefansdottir, Gardar Sveinbjornsson, Vinicius Tragante, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur L. Norddahl, Ingileif Jonsdottir () and Kari Stefansson ()
Additional contact information
Thorunn A. Olafsdottir: deCODE genetics/Amgen, Inc.
Fannar Theodors: deCODE genetics/Amgen, Inc.
Kristbjorg Bjarnadottir: deCODE genetics/Amgen, Inc.
Unnur Steina Bjornsdottir: The National University Hospital of Iceland
Arna B. Agustsdottir: deCODE genetics/Amgen, Inc.
Olafur A. Stefansson: deCODE genetics/Amgen, Inc.
Erna V. Ivarsdottir: deCODE genetics/Amgen, Inc.
Jon K. Sigurdsson: deCODE genetics/Amgen, Inc.
Stefania Benonisdottir: deCODE genetics/Amgen, Inc.
Gudmundur I. Eyjolfsson: The Laboratory in Mjodd, RAM
David Gislason: The Medical Center Mjodd
Thorarinn Gislason: University of Iceland
Steinunn Guðmundsdóttir: deCODE genetics/Amgen, Inc.
Arnaldur Gylfason: deCODE genetics/Amgen, Inc.
Bjarni V. Halldorsson: deCODE genetics/Amgen, Inc.
Gisli H. Halldorsson: deCODE genetics/Amgen, Inc.
Thorhildur Juliusdottir: deCODE genetics/Amgen, Inc.
Anna M. Kristinsdottir: deCODE genetics/Amgen, Inc.
Dora Ludviksdottir: University of Iceland
Bjorn R. Ludviksson: University of Iceland
Gisli Masson: deCODE genetics/Amgen, Inc.
Kristjan Norland: deCODE genetics/Amgen, Inc.
Pall T. Onundarson: University of Iceland
Isleifur Olafsson: The National University Hospital of Iceland
Olof Sigurdardottir: University of Iceland
Lilja Stefansdottir: deCODE genetics/Amgen, Inc.
Gardar Sveinbjornsson: deCODE genetics/Amgen, Inc.
Vinicius Tragante: deCODE genetics/Amgen, Inc.
Daniel F. Gudbjartsson: deCODE genetics/Amgen, Inc.
Gudmar Thorleifsson: deCODE genetics/Amgen, Inc.
Patrick Sulem: deCODE genetics/Amgen, Inc.
Unnur Thorsteinsdottir: deCODE genetics/Amgen, Inc.
Gudmundur L. Norddahl: deCODE genetics/Amgen, Inc.
Ingileif Jonsdottir: deCODE genetics/Amgen, Inc.
Kari Stefansson: deCODE genetics/Amgen, Inc.

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14144-8

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