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

Sarah Grosche, Ingo Marenholz, Jorge Esparza-Gordillo, Aleix Arnau-Soler, Erola Pairo-Castineira, Franz Rüschendorf, Tarunveer S. Ahluwalia, Catarina Almqvist, Andreas Arnold, Hansjörg Baurecht, Hans Bisgaard, Klaus Bønnelykke, Sara J. Brown, Mariona Bustamante, John A. Curtin, Adnan Custovic, Shyamali C. Dharmage, Ana Esplugues, Mario Falchi, Dietmar Fernandez-Orth, Manuel A. R. Ferreira, Andre Franke, Sascha Gerdes, Christian Gieger, Hakon Hakonarson, Patrick G. Holt, Georg Homuth, Norbert Hubner, Pirro G. Hysi, Marjo-Riitta Jarvelin, Robert Karlsson, Gerard H. Koppelman, Susanne Lau, Manuel Lutz, Patrik K. E. Magnusson, Guy B. Marks, Martina Müller-Nurasyid, Markus M. Nöthen, Lavinia Paternoster, Craig E. Pennell, Annette Peters, Konrad Rawlik, Colin F. Robertson, Elke Rodriguez, Sylvain Sebert, Angela Simpson, Patrick M. A. Sleiman, Marie Standl, Dora Stölzl, Konstantin Strauch, Agnieszka Szwajda, Albert Tenesa, Philip J. Thompson, Vilhelmina Ullemar, Alessia Visconti, Judith M. Vonk, Carol A. Wang, Stephan Weidinger, Matthias Wielscher, Catherine L. Worth, Chen-Jian Xu and Young-Ae Lee ()
Additional contact information
Sarah Grosche: Max-Delbrück-Center (MDC) for Molecular Medicine
Ingo Marenholz: Max-Delbrück-Center (MDC) for Molecular Medicine
Jorge Esparza-Gordillo: Max-Delbrück-Center (MDC) for Molecular Medicine
Aleix Arnau-Soler: Max-Delbrück-Center (MDC) for Molecular Medicine
Erola Pairo-Castineira: University of Edinburgh
Franz Rüschendorf: Max-Delbrück-Center (MDC) for Molecular Medicine
Tarunveer S. Ahluwalia: Herlev and Gentofte Hospital, University of Copenhagen
Catarina Almqvist: Karolinska Institute
Andreas Arnold: University Medicine Greifswald
Hansjörg Baurecht: University Hospital Schleswig-Holstein
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
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
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
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
Agnieszka Szwajda: Karolinska Institute
Albert Tenesa: University of Edinburgh
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
Young-Ae Lee: Max-Delbrück-Center (MDC) for Molecular Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26783-x

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