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Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Listed:
  • Sarah Grosche

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Charité University Medical Center
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Ingo Marenholz

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Charité University Medical Center)

  • Jorge Esparza-Gordillo

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Charité University Medical Center
    GlaxoSmithKline)

  • Aleix Arnau-Soler

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Charité University Medical Center)

  • Erola Pairo-Castineira

    (University of Edinburgh
    University of Edinburgh, Western General Hospital)

  • Franz Rüschendorf

    (Max-Delbrück-Center (MDC) for Molecular Medicine)

  • Tarunveer S. Ahluwalia

    (Herlev and Gentofte Hospital, University of Copenhagen
    Steno Diabetes Center Copenhagen)

  • Catarina Almqvist

    (Karolinska Institute
    Karolinska University Hospital)

  • Andreas Arnold

    (University Medicine Greifswald)

  • Hansjörg Baurecht

    (University Hospital Schleswig-Holstein
    University Regensburg)

  • Hans Bisgaard

    (Herlev and Gentofte Hospital, University of Copenhagen)

  • Klaus Bønnelykke

    (Herlev and Gentofte Hospital, University of Copenhagen)

  • Sara J. Brown

    (The University of Edinburgh)

  • Mariona Bustamante

    (ISGlobal, Centre for Research in Environmental Epidemiology (CREAL))

  • John A. Curtin

    (The University of Manchester, Manchester Academic Health Science Centre and Manchester University NHS Foundation Trust)

  • Adnan Custovic

    (Imperial College London)

  • Shyamali C. Dharmage

    (The University of Melbourne)

  • Ana Esplugues

    (University of Valencia, FISABIO-University Jaume I-University of Valencia Joint Research Unit of Epidemiology and Environmental Health, CIBERESP)

  • Mario Falchi

    (King’s College London)

  • Dietmar Fernandez-Orth

    (ISGlobal, Centre for Research in Environmental Epidemiology (CREAL))

  • Manuel A. R. Ferreira

    (QIMR Berghofer Medical Research Institute)

  • Andre Franke

    (Christian-Albrechts-University of Kiel)

  • Sascha Gerdes

    (University Hospital Schleswig-Holstein)

  • Christian Gieger

    (Helmholtz Center Munich – German Research Center for Environmental Health)

  • Hakon Hakonarson

    (University of Pennsylvania)

  • Patrick G. Holt

    (The University of Western Australia)

  • Georg Homuth

    (Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald)

  • Norbert Hubner

    (Max-Delbrück-Center (MDC) for Molecular Medicine)

  • Pirro G. Hysi

    (King’s College London)

  • Marjo-Riitta Jarvelin

    (MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London
    University of Oulu
    University of Oulu)

  • Robert Karlsson

    (Karolinska Institute)

  • Gerard H. Koppelman

    (University of Groningen, University Medical Center Groningen, GRIAC Research Institute)

  • Susanne Lau

    (Immunology and Intensive Care Medicine, Charité University Medical Center)

  • Manuel Lutz

    (Helmholtz Center Munich–German Research Center for Environmental Health)

  • Patrik K. E. Magnusson

    (Karolinska Institute)

  • Guy B. Marks

    (University of Sydney)

  • Martina Müller-Nurasyid

    (Helmholtz Center Munich–German Research Center for Environmental Health
    Faculty of Medicine, LMU Munich
    University Medical Center, Johannes Gutenberg University)

  • Markus M. Nöthen

    (University of Bonn, School of Medicine & University Hospital Bonn)

  • Lavinia Paternoster

    (Bristol Medical School, University of Bristol)

  • Craig E. Pennell

    (The University of Newcastle)

  • Annette Peters

    (Helmholtz Center Munich–German Research Center for Environmental Health)

  • Konrad Rawlik

    (University of Edinburgh)

  • Colin F. Robertson

    (Murdoch Children’s Research Institute)

  • Elke Rodriguez

    (University Hospital Schleswig-Holstein)

  • Sylvain Sebert

    (MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London
    University of Oulu
    University of Oulu)

  • Angela Simpson

    (The University of Manchester, Manchester Academic Health Science Centre and Manchester University NHS Foundation Trust)

  • Patrick M. A. Sleiman

    (University of Pennsylvania)

  • Marie Standl

    (Helmholtz Center Munich–German Research Center for Environmental Health)

  • Dora Stölzl

    (University Hospital Schleswig-Holstein)

  • Konstantin Strauch

    (Helmholtz Center Munich–German Research Center for Environmental Health
    Faculty of Medicine, LMU Munich
    University Medical Center, Johannes Gutenberg University)

  • Agnieszka Szwajda

    (Karolinska Institute)

  • Albert Tenesa

    (University of Edinburgh
    University of Edinburgh, Western General Hospital
    Usher Institute of Population Health Sciences and Informatics)

  • Philip J. Thompson

    (University of Western Australia)

  • Vilhelmina Ullemar

    (Karolinska Institute)

  • Alessia Visconti

    (King’s College London)

  • Judith M. Vonk

    (University of Groningen, University Medical Center Groningen, GRIAC Research Institute)

  • Carol A. Wang

    (The University of Newcastle)

  • Stephan Weidinger

    (University Hospital Schleswig-Holstein)

  • Matthias Wielscher

    (MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London)

  • Catherine L. Worth

    (Max-Delbrück-Center (MDC) for Molecular Medicine)

  • Chen-Jian Xu

    (University of Groningen, University Medical Center Groningen, GRIAC Research Institute
    Centre for individualized infection medicine (CIIM), Hannover Medical School)

  • Young-Ae Lee

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Charité University Medical Center)

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Suggested Citation

  • Sarah Grosche & Ingo Marenholz & Jorge Esparza-Gordillo & Aleix Arnau-Soler & Erola Pairo-Castineira & Franz Rüschendorf & Tarunveer S. Ahluwalia & Catarina Almqvist & Andreas Arnold & Hansjörg Baurec, 2021. "Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26783-x
    DOI: 10.1038/s41467-021-26783-x
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    References listed on IDEAS

    as
    1. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    2. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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