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

Australian Asthma Genetics Consortium (AAGC)

doi:10.1038/s41467-021-26783-x

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

Australian Asthma Genetics Consortium (AAGC)

Max-Delbrück-Center (MDC) for Molecular Medicine
University of Edinburgh
Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Unit of Chronic Inflammation, Institute of Environmental Medicine, Karolinska Institute, Sweden.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
University Hospital Schleswig- Holstein
ISGlobal (Barcelona Institute for Global Health), Barcelona, Catalonia, Spain
Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK; Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
Department of Materials, Imperial College London, London SW7 2AZ, United Kingdom; Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom; Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom.
University of Melbourne
Catholic University of Valencia, University Clinic Hospital, Valencia, Spain.
Department of Twins Research and Genetic Epidemiology
King's College London
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Institute of Immunology, Christian-Albrechts University of Kiel, Kiel, Germany.
1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] DZHK (Deutsches Forschungszentrum für Herz-Kreislauferkrankungen-German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. [3] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; UWA Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Western Australia, Australia.
Department of Gynaecological Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Cardiology and Pneumology, Charité Campus Benjamin Franklin, University Medical Center Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
1] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians Universität, Neuherberg, Germany.
Department of Biostatistics, University of Sydney, School of Public Health, Sydney, New South Wales, Australia
Department of Epileptology, University Hospital Bonn, Bonn, Germany
University of Bristol
Hunter Medical Research Institute, New South Wales, Australia; Priority Research Center for Health Behaviour, The University of Newcastle, New South Wales, Australia; School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Institute of Epidemiology I and Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology and , Klinikum Grosshadern, 81377 Munich, Germany and.
Royal Childrens Hosp, Murdoch Children's Research Institute, Royal Children's Hospital Brisbane, Murdoch Childrens Res Inst

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

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.

Original language	English
Article number	6618
Pages (from-to)	6618
Number of pages	1
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26783-x
Publication status	Published - 16 Nov 2021

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@article{57dd20e1d6ae436a8a5f38c30b202744,

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

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.",

author = "{Australian Asthma Genetics Consortium (AAGC)} and Sarah Grosche and Ingo Marenholz and Jorge Esparza-Gordillo and Aleix Arnau-Soler and Erola Pairo-Castineira and Franz R{\"u}schendorf and Ahluwalia, {Tarunveer S} and Catarina Almqvist and Andreas Arnold and Hansj{\"o}rg Baurecht and Hans Bisgaard and Klaus B{\o}nnelykke and Brown, {Sara J} and Mariona Bustamante and Curtin, {John A} and Adnan Custovic and Dharmage, {Shyamali C} and Ana Esplugues and Mario Falchi and Dietmar Fernandez-Orth and Ferreira, {Manuel A R} and Andre Franke and Sascha Gerdes and Christian Gieger and Hakon Hakonarson and Holt, {Patrick G} and Georg Homuth and Norbert Hubner and Hysi, {Pirro G} and Marjo-Riitta Jarvelin and Robert Karlsson and Koppelman, {Gerard H} and Susanne Lau and Manuel Lutz and Magnusson, {Patrik K E} and Marks, {Guy B} and Martina M{\"u}ller-Nurasyid and N{\"o}then, {Markus M} and Lavinia Paternoster and Pennell, {Craig E} and Annette Peters and Konrad Rawlik and Robertson, {Colin F} and Elke Rodriguez and Sylvain Sebert and Angela Simpson and Sleiman, {Patrick M A} and Marie Standl and Dora St{\"o}lzl and Alessia Visconti",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = nov,

day = "16",

doi = "10.1038/s41467-021-26783-x",

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journal = "Nature Communications",

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AU - Australian Asthma Genetics Consortium (AAGC)

AU - Grosche, Sarah

AU - Marenholz, Ingo

AU - Esparza-Gordillo, Jorge

AU - Arnau-Soler, Aleix

AU - Pairo-Castineira, Erola

AU - Rüschendorf, Franz

AU - Ahluwalia, Tarunveer S

AU - Almqvist, Catarina

AU - Arnold, Andreas

AU - Baurecht, Hansjörg

AU - Bisgaard, Hans

AU - Bønnelykke, Klaus

AU - Brown, Sara J

AU - Bustamante, Mariona

AU - Curtin, John A

AU - Custovic, Adnan

AU - Dharmage, Shyamali C

AU - Esplugues, Ana

AU - Falchi, Mario

AU - Fernandez-Orth, Dietmar

AU - Ferreira, Manuel A R

AU - Franke, Andre

AU - Gerdes, Sascha

AU - Gieger, Christian

AU - Hakonarson, Hakon

AU - Holt, Patrick G

AU - Homuth, Georg

AU - Hubner, Norbert

AU - Hysi, Pirro G

AU - Jarvelin, Marjo-Riitta

AU - Karlsson, Robert

AU - Koppelman, Gerard H

AU - Lau, Susanne

AU - Lutz, Manuel

AU - Magnusson, Patrik K E

AU - Marks, Guy B

AU - Müller-Nurasyid, Martina

AU - Nöthen, Markus M

AU - Paternoster, Lavinia

AU - Pennell, Craig E

AU - Peters, Annette

AU - Rawlik, Konrad

AU - Robertson, Colin F

AU - Rodriguez, Elke

AU - Sebert, Sylvain

AU - Simpson, Angela

AU - Sleiman, Patrick M A

AU - Standl, Marie

AU - Stölzl, Dora

AU - Visconti, Alessia

PY - 2021/11/16

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

Abstract

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