TY - JOUR
T1 - Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression
AU - Mucha, Sören
AU - Baurecht, Hansjörg
AU - Novak, Natalija
AU - Rodríguez, Elke
AU - Bej, Saptarshi
AU - Mayr, Gabriele
AU - Emmert, Hila
AU - Stölzl, Dora
AU - Gerdes, Sascha
AU - Degenhardt, Frauke
AU - Hübenthal, Matthias
AU - Ellinghaus, Eva
AU - Jung, Eun Suk
AU - Kässens, Jan Christian
AU - Wienbrandt, Lars
AU - Lieb, Wolfgang
AU - Müller-Nurasyid, Martina
AU - Hotze, Melanie
AU - Dand, Nick
AU - Grosche, Sarah
AU - Marenholz, Ingo
AU - Arnold, Andreas
AU - Homuth, Georg
AU - Schmidt, Carsten O
AU - Wehkamp, Ulrike
AU - Nöthen, Markus M
AU - Hoffmann, Per
AU - Paternoster, Lavinia
AU - Standl, Marie
AU - Bønnelykke, Klaus
AU - Ahluwalia, Tarunveer S
AU - Bisgaard, Hans
AU - Peters, Annette
AU - Gieger, Christian
AU - Waldenberger, Melanie
AU - Schulz, Holger
AU - Strauch, Konstantin
AU - Werfel, Thomas
AU - Lee, Young-Ae
AU - Wolfien, Markus
AU - Rosenstiel, Philip
AU - Wolkenhauer, Olaf
AU - Schreiber, Stefan
AU - Franke, Andre
AU - Weidinger, Stephan
AU - Ellinghaus, David
AU - Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium
N1 - Copyright © 2019. Published by Elsevier Inc.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Adult
KW - Cohort Studies
KW - Dermatitis, Atopic/genetics
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Orexin Receptors/genetics
KW - Organ Specificity
KW - Phosphoproteins/genetics
KW - Polymorphism, Genetic
KW - Risk
KW - Skin/metabolism
KW - Transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85076544401&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2019.10.030
DO - 10.1016/j.jaci.2019.10.030
M3 - Journal article
C2 - 31707051
SN - 0091-6749
VL - 145
SP - 1208
EP - 1218
JO - The Journal of allergy and clinical immunology
JF - The Journal of allergy and clinical immunology
IS - 4
ER -