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J Allergy Clin Immunol. 2019 Nov 7. pii: S0091-6749(19)31480-0. doi: 10.1016/j.jaci.2019.10.030. [Epub ahead of print]

Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression.

Author information

1
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
2
Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department for Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
3
Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
4
Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
5
Department of Systems Biology and Bioinformatics, University of Rostock, Germany.
6
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
7
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
8
Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany.
9
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
10
School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
11
Pediatric Allergology, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany.
12
Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany.
13
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
14
Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany.
15
Institute of Human Genetics, University of Bonn, Bonn, Germany.
16
Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
17
Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
18
Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, Denmark.
19
Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, Denmark; Steno Diabetes Center Copenhagen, Gentofte 2820, Denmark.
20
Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
21
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany.
22
Steno Diabetes Center Copenhagen, Gentofte 2820, Denmark.
23
Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany; School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
24
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
25
Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: sweider@dermatology.uni-kiel.de.
26
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. Electronic address: d.ellinghaus@ikmb.uni-kiel.de.

Abstract

BACKGROUND:

15% of atopic dermatitis liability-scale heritability could be attributed to 31 susceptibility loci identified by genome-wide association studies, with only three of them (IL13, IL6R, and FLG) resolved to protein-coding variants.

OBJECTIVE:

We examined whether a significant portion of unexplained atopic dermatitis heritability is further explained by low-frequency and rare variants in gene coding sequence.

METHODS:

We evaluated common, low-frequency and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 controls, combined with whole transcriptome data on lesional, non-lesional and healthy skin samples of 27 patients and 38 controls.

RESULTS:

Additional 12.56% (s.e. 0.74%) of atopic dermatitis heritability is explained by rare protein-coding variation. We identified Docking protein 2 (DOK2) and CD200 Receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with atopic dermatitis are further enriched in five genes (IL4R, IL13, JAK1, JAK2, TYK2) of the IL13 pathway, all of which are targets for novel systemic atopic dermatitis therapeutics. Multiomics-based network and RNA-Sequencing analysis revealed DOK2 as a central hub interacting, among others, with CD200R1, IL6R and STAT3. Multi-tissue gene expression profile analysis for 53 tissue types from GTEx showed that disease-associated protein-coding variants exert their greatest effect in skin tissues.

CONCLUSION:

Our discoveries highlight a major role of rare coding variants in atopic dermatitis acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

KEYWORDS:

Atopic dermatitis; RNA-Seq; exome chip association analysis; network analysis; protein sequence and structural domain analysis

PMID:
31707051
DOI:
10.1016/j.jaci.2019.10.030

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