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, Young-Ae Lee

Journal: Nature communications 2021;12(1):6618

PMID: 34785669

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.

© 2021. The Author(s).

Address: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.; Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.; GlaxoSmithKline, Stevenage, UK.; Roslin Institute, University of Edinburgh, Edinburgh, UK.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.; Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.; Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany.; Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Kiel, Germany.; Department of Epidemiology and Preventive Medicine, University Regensburg, Regensburg, Germany.; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.; Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre and Manchester University NHS Foundation Trust, Manchester, UK.; National Lung and Heart Institute, Imperial College London, London, UK.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.; Nursing School, University of Valencia, FISABIO-University Jaume I-University of Valencia Joint Research Unit of Epidemiology and Environmental Health, CIBERESP, Valencia, Spain.; Department of Twins Research and Genetic Epidemiology, King's College London, London, UK.; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.; Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Kiel, Germany.; Research Unit Molecular Epidemiology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.; Center for Applied Genomics, Children's Hospital of Philadelphia, and Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Telethon Kids Institute, The University of Western Australia, Perth, Australia.; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.; Biocenter Oulu, University of Oulu, Oulu, Finland.; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.; Department of Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands.; Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité University Medical Center, Berlin, Germany.; Institute of Genetic Epidemiology, Helmholtz Center Munich-German Research Center for Environmental Health, Neuherberg, Germany.; Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia.; Institute of Genetic Epidemiology, Helmholtz Center Munich-German Research Center for Environmental Health, Neuherberg, Germany.; Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany.; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, Australia.; Institute of Epidemiology, Helmholtz Center Munich-German Research Center for Environmental Health, Neuherberg, Germany.; Roslin Institute, University of Edinburgh, Edinburgh, UK.; Respiratory Research, Murdoch Children's Research Institute, Melbourne, Australia.; Roslin Institute, University of Edinburgh, Edinburgh, UK.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK.; Institute for Respiratory Health and Centre for Respiratory Health, School of Biomedical Sciences, University of Western Australia, Nedlands, Australia.; Department of Epidemiology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands.; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.; Department of Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands.; Department of Gastroenterology, Hepatology and Endocrinology, Centre for individualized infection medicine (CIIM), Hannover Medical School, Hannover, Germany.; Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany. [email protected].; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany. [email protected].
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