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

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Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. / Mucha, Sören; Baurecht, Hansjörg; Novak, Natalija; Rodríguez, Elke; Bej, Saptarshi; Mayr, Gabriele; Emmert, Hila; Stölzl, Dora; Gerdes, Sascha; Jung, Eun Suk; Degenhardt, Frauke; Hübenthal, Matthias; Ellinghaus, Eva; Kässens, Jan Christian; Wienbrandt, Lars; Lieb, Wolfgang; Müller-Nurasyid, Martina; Hotze, Melanie; Dand, Nick; Grosche, Sarah; Marenholz, Ingo; Arnold, Andreas; Homuth, Georg; Schmidt, Carsten O.; Wehkamp, Ulrike; Nöthen, Markus M.; Hoffmann, Per; Paternoster, Lavinia; Standl, Marie; Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium ; Bønnelykke, Klaus; Ahluwalia, Tarunveer S.; Bisgaard, Hans; Peters, Annette; Gieger, Christian; Waldenberger, Melanie; Schulz, Holger; Strauch, Konstantin; Werfel, Thomas; Lee, Young Ae; Wolfien, Markus; Rosenstiel, Philip; Wolkenhauer, Olaf; Schreiber, Stefan; Franke, Andre; Weidinger, Stephan; Ellinghaus, David.

In: Journal of Allergy and Clinical Immunology, Vol. 145, No. 4, 04.2020, p. 1208-1218.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Mucha, S, Baurecht, H, Novak, N, Rodríguez, E, Bej, S, Mayr, G, Emmert, H, Stölzl, D, Gerdes, S, Jung, ES, Degenhardt, F, Hübenthal, M, Ellinghaus, E, Kässens, JC, Wienbrandt, L, Lieb, W, Müller-Nurasyid, M, Hotze, M, Dand, N, Grosche, S, Marenholz, I, Arnold, A, Homuth, G, Schmidt, CO, Wehkamp, U, Nöthen, MM, Hoffmann, P, Paternoster, L, Standl, M, Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium, Bønnelykke, K, Ahluwalia, TS, Bisgaard, H, Peters, A, Gieger, C, Waldenberger, M, Schulz, H, Strauch, K, Werfel, T, Lee, YA, Wolfien, M, Rosenstiel, P, Wolkenhauer, O, Schreiber, S, Franke, A, Weidinger, S & Ellinghaus, D 2020, 'Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression', Journal of Allergy and Clinical Immunology, vol. 145, no. 4, pp. 1208-1218. https://doi.org/10.1016/j.jaci.2019.10.030

APA

Mucha, S., Baurecht, H., Novak, N., Rodríguez, E., Bej, S., Mayr, G., Emmert, H., Stölzl, D., Gerdes, S., Jung, E. S., Degenhardt, F., Hübenthal, M., Ellinghaus, E., Kässens, J. C., Wienbrandt, L., Lieb, W., Müller-Nurasyid, M., Hotze, M., Dand, N., ... Ellinghaus, D. (2020). Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. Journal of Allergy and Clinical Immunology, 145(4), 1208-1218. https://doi.org/10.1016/j.jaci.2019.10.030

Vancouver

Mucha S, Baurecht H, Novak N, Rodríguez E, Bej S, Mayr G et al. Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. Journal of Allergy and Clinical Immunology. 2020 Apr;145(4):1208-1218. https://doi.org/10.1016/j.jaci.2019.10.030

Author

Mucha, Sören ; Baurecht, Hansjörg ; Novak, Natalija ; Rodríguez, Elke ; Bej, Saptarshi ; Mayr, Gabriele ; Emmert, Hila ; Stölzl, Dora ; Gerdes, Sascha ; Jung, Eun Suk ; Degenhardt, Frauke ; Hübenthal, Matthias ; Ellinghaus, Eva ; Kässens, Jan Christian ; Wienbrandt, Lars ; Lieb, Wolfgang ; Müller-Nurasyid, Martina ; Hotze, Melanie ; Dand, Nick ; Grosche, Sarah ; Marenholz, Ingo ; Arnold, Andreas ; Homuth, Georg ; Schmidt, Carsten O. ; Wehkamp, Ulrike ; Nöthen, Markus M. ; Hoffmann, Per ; Paternoster, Lavinia ; Standl, Marie ; Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium ; Bønnelykke, Klaus ; Ahluwalia, Tarunveer S. ; Bisgaard, Hans ; Peters, Annette ; Gieger, Christian ; Waldenberger, Melanie ; Schulz, Holger ; Strauch, Konstantin ; Werfel, Thomas ; Lee, Young Ae ; Wolfien, Markus ; Rosenstiel, Philip ; Wolkenhauer, Olaf ; Schreiber, Stefan ; Franke, Andre ; Weidinger, Stephan ; Ellinghaus, David. / Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. In: Journal of Allergy and Clinical Immunology. 2020 ; Vol. 145, No. 4. pp. 1208-1218.

Bibtex

@article{4a1fbe1270a54676bcf6ad3de4cf8fb2,
title = "Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression",
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.",
keywords = "Atopic dermatitis, exome chip association analysis, network analysis, protein sequence and structural domain analysis, RNA sequencing",
author = "S{\"o}ren Mucha and Hansj{\"o}rg Baurecht and Natalija Novak and Elke Rodr{\'i}guez and Saptarshi Bej and Gabriele Mayr and Hila Emmert and Dora St{\"o}lzl and Sascha Gerdes and Jung, {Eun Suk} and Frauke Degenhardt and Matthias H{\"u}benthal and Eva Ellinghaus and K{\"a}ssens, {Jan Christian} and Lars Wienbrandt and Wolfgang Lieb and Martina M{\"u}ller-Nurasyid and Melanie Hotze and Nick Dand and Sarah Grosche and Ingo Marenholz and Andreas Arnold and Georg Homuth and Schmidt, {Carsten O.} and Ulrike Wehkamp and N{\"o}then, {Markus M.} and Per Hoffmann and Lavinia Paternoster and Marie Standl and {Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium} and Klaus B{\o}nnelykke and Ahluwalia, {Tarunveer S.} and Hans Bisgaard and Annette Peters and Christian Gieger and Melanie Waldenberger and Holger Schulz and Konstantin Strauch and Thomas Werfel and Lee, {Young Ae} and Markus Wolfien and Philip Rosenstiel and Olaf Wolkenhauer and Stefan Schreiber and Andre Franke and Stephan Weidinger and David Ellinghaus",
year = "2020",
month = apr,
doi = "10.1016/j.jaci.2019.10.030",
language = "English",
volume = "145",
pages = "1208--1218",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "4",

}

RIS

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 - Jung, Eun Suk

AU - Degenhardt, Frauke

AU - Hübenthal, Matthias

AU - Ellinghaus, Eva

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 - Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium

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

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 - Atopic dermatitis

KW - exome chip association analysis

KW - network analysis

KW - protein sequence and structural domain analysis

KW - RNA sequencing

U2 - 10.1016/j.jaci.2019.10.030

DO - 10.1016/j.jaci.2019.10.030

M3 - Journal article

C2 - 31707051

AN - SCOPUS:85076544401

VL - 145

SP - 1208

EP - 1218

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 4

ER -

ID: 240410461