Mucha, Soren and Baurecht, Hansjorg and Novak, Natalija and Rodriguez, Elke and Bej, Saptarshi and Mayr, Gabriele and Emmert, Hila and Stoelzl, Dora and Gerdes, Sascha and Jung, Eun Suk and Degenhardt, Frauke and Huebenthal, Matthias and Ellinghaus, Eva and Kaessens, Jan Christian and Wienbrandt, Lars and Lieb, Wolfgang and Mueller-Nurasyid, Martina and Hotze, Melanie and Dand, Nick and Grosche, Sarah and Marenholz, Ingo and Arnold, Andreas and Homuth, Georg and Schmidt, Carsten O. and Wehkamp, Ulrike and Nothen, Markus M. and Hoffmann, Per and Paternoster, Lavinia and Standl, Marie and Bonnelykke, Klaus and Ahluwalia, Tarunveer S. and Bisgaard, Hans and Peters, Annette and Gieger, Christian and Waldenberger, Melanie and Schulz, Holger and Strauch, Konstantin and Werfel, Thomas and Lee, Young-Ae and Wolfien, Markus and Rosenstiel, Philip and Wolkenhauer, Olaf and Schreiber, Stefan and Franke, Andre and Weidinger, Stephan and Ellinghaus, David (2020) Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 145 (4). pp. 1208-1218. ISSN 0091-6749, 1097-6825
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; NEGATIVE REGULATORS; ALLERGIC DISEASE; CELL DEVELOPMENT; ROLES; DOK-2; RASGAP; ASTHMA; FAMILY; Atopic dermatitis; exome chip association analysis; network analysis; protein sequence and structural domain analysis; RNA sequencing |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Epidemiologie und Präventivmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Mar 2021 06:45 |
| Last Modified: | 29 Mar 2021 06:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44847 |
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