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

 Sören Mucha  ;  Hansjörg Baurecht  ;  Natalija Novak  ;  Elke Rodríguez  ;  Saptarshi Bej  ;  Gabriele Mayr  ;  Hila Emmert  ;  Dora Stölzl  ;  Sascha Gerdes  ;  Eun Suk Jung  ;  Frauke Degenhardt  ;  Matthias Hübenthal  ;  Eva Ellinghaus  ;  Jan Christian Kässens  ;  Lars Wienbrandt  ;  Wolfgang Lieb  ;  Martina Müller-Nurasyid  ;  Melanie Hotze  ;  Nick Dand  ;  Sarah Grosche  ;  Ingo Marenholz  ;  Andreas Arnold  ;  Georg Homuth  ;  Carsten O Schmidt  ;  Ulrike Wehkamp  ;  Markus M Nöthen  ;  Per Hoffmann  ;  Lavinia Paternoster  ;  Marie Standl  ;  Klaus Bønnelykke  ;  Tarunveer S Ahluwalia  ;  Hans Bisgaard  ;  Annette Peters  ;  Christian Gieger  ;  Melanie Waldenberger  ;  Holger Schulz  ;  Konstantin Strauch  ;  Thomas Werfel  ;  Young-Ae Lee  ;  Markus Wolfien  ;  Philip Rosenstiel  ;  Olaf Wolkenhauer  ;  Stefan Schreiber  ;  Andre Franke  ;  Stephan Weidinger  ;  David Ellinghaus 
 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol.145(4) : 1208-1218, 2020-04 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing / genetics* ; Adult ; Cohort Studies ; Dermatitis, Atopic / genetics* ; Filaggrin Proteins ; Gene Frequency ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype* ; Humans ; Orexin Receptors / genetics* ; Organ Specificity ; Phosphoproteins / genetics* ; Polymorphism, Genetic ; Risk ; Skin / metabolism* ; Transcriptome
Atopic dermatitis ; exome chip association analysis ; network analysis ; protein sequence and structural domain analysis ; RNA sequencing
Background: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. Objective: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the 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 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. Results: An additional 12.56% (SE, 0.74%) of AD 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 AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project 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 AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Jung, Eun Suk(정은석)
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