Sören Mucha1, Hansjörg Baurecht2, Natalija Novak3, Elke Rodríguez4, Saptarshi Bej5, Gabriele Mayr1, Hila Emmert4, Dora Stölzl4, Sascha Gerdes4, Eun Suk Jung6, Frauke Degenhardt1, Matthias Hübenthal7, Eva Ellinghaus1, Jan Christian Kässens1, Lars Wienbrandt1, Wolfgang Lieb8, Martina Müller-Nurasyid9, Melanie Hotze4, Nick Dand10, Sarah Grosche11, Ingo Marenholz11, Andreas Arnold12, Georg Homuth13, Carsten O Schmidt14, Ulrike Wehkamp4, Markus M Nöthen15, Per Hoffmann15, Lavinia Paternoster16, Marie Standl17, Klaus Bønnelykke18, Tarunveer S Ahluwalia19, Hans Bisgaard18, Annette Peters17, Christian Gieger20, Melanie Waldenberger20, Holger Schulz17, Konstantin Strauch21, Thomas Werfel22, Young-Ae Lee23, Markus Wolfien5, Philip Rosenstiel1, Olaf Wolkenhauer5, Stefan Schreiber24, Andre Franke1, Stephan Weidinger25, David Ellinghaus26. 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 Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. 7. 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. 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, Ludwig-Maximilians-University Munich, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany. 10. School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. 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, and the School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom. 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, Gentofte, Denmark. 19. Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, Gentofte, Denmark; Steno Diabetes Center Copenhagen, Gentofte, 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, Ludwig-Maximilians-University Munich, Germany. 22. Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Dermatology and Allergy, Division of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany. 23. Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. 24. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany; First Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany. 25. Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: sweidinger@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: 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.
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.
Authors: Aleksejs Sazonovs; Christine R Stevens; Guhan R Venkataraman; Kai Yuan; Brandon Avila; Maria T Abreu; Tariq Ahmad; Matthieu Allez; Ashwin N Ananthakrishnan; Gil Atzmon; Aris Baras; Jeffrey C Barrett; Nir Barzilai; Laurent Beaugerie; Ashley Beecham; Charles N Bernstein; Alain Bitton; Bernd Bokemeyer; Andrew Chan; Daniel Chung; Isabelle Cleynen; Jacques Cosnes; David J Cutler; Allan Daly; Oriana M Damas; Lisa W Datta; Noor Dawany; Marcella Devoto; Sheila Dodge; Eva Ellinghaus; Laura Fachal; Martti Farkkila; William Faubion; Manuel Ferreira; Denis Franchimont; Stacey B Gabriel; Tian Ge; Michel Georges; Kyle Gettler; Mamta Giri; Benjamin Glaser; Siegfried Goerg; Philippe Goyette; Daniel Graham; Eija Hämäläinen; Talin Haritunians; Graham A Heap; Mikko Hiltunen; Marc Hoeppner; Julie E Horowitz; Peter Irving; Vivek Iyer; Chaim Jalas; Judith Kelsen; Hamed Khalili; Barbara S Kirschner; Kimmo Kontula; Jukka T Koskela; Subra Kugathasan; Juozas Kupcinskas; Christopher A Lamb; Matthias Laudes; Chloé Lévesque; Adam P Levine; James D Lewis; Claire Liefferinckx; Britt-Sabina Loescher; Edouard Louis; John Mansfield; Sandra May; Jacob L McCauley; Emebet Mengesha; Myriam Mni; Paul Moayyedi; Christopher J Moran; Rodney D Newberry; Sirimon O'Charoen; David T Okou; Bas Oldenburg; Harry Ostrer; Aarno Palotie; Jean Paquette; Joel Pekow; Inga Peter; Marieke J Pierik; Cyriel Y Ponsioen; Nikolas Pontikos; Natalie Prescott; Ann E Pulver; Souad Rahmouni; Daniel L Rice; Päivi Saavalainen; Bruce Sands; R Balfour Sartor; Elena R Schiff; Stefan Schreiber; L Philip Schumm; Anthony W Segal; Philippe Seksik; Rasha Shawky; Shehzad Z Sheikh; Mark S Silverberg; Alison Simmons; Jurgita Skeiceviciene; Harry Sokol; Matthew Solomonson; Hari Somineni; Dylan Sun; Stephan Targan; Dan Turner; Holm H Uhlig; Andrea E van der Meulen; Séverine Vermeire; Sare Verstockt; Michiel D Voskuil; Harland S Winter; Justine Young; Richard H Duerr; Andre Franke; Steven R Brant; Judy Cho; Rinse K Weersma; Miles Parkes; Ramnik J Xavier; Manuel A Rivas; John D Rioux; Dermot P B McGovern; Hailiang Huang; Carl A Anderson; Mark J Daly Journal: Nat Genet Date: 2022-08-29 Impact factor: 41.307
Authors: Tarunveer S Ahluwalia; Bram P Prins; Mohammadreza Abdollahi; Nicola J Armstrong; Stella Aslibekyan; Lisa Bain; Barbara Jefferis; Jens Baumert; Marian Beekman; Yoav Ben-Shlomo; Joshua C Bis; Braxton D Mitchell; Eco de Geus; Graciela E Delgado; Diana Marek; Joel Eriksson; Eero Kajantie; Stavroula Kanoni; John P Kemp; Chen Lu; Riccardo E Marioni; Stela McLachlan; Yuri Milaneschi; Ilja M Nolte; Alexandros M Petrelis; Eleonora Porcu; Maria Sabater-Lleal; Elnaz Naderi; Ilkka Seppälä; Tina Shah; Gaurav Singhal; Marie Standl; Alexander Teumer; Anbupalam Thalamuthu; Elisabeth Thiering; Stella Trompet; Christie M Ballantyne; Emelia J Benjamin; Juan P Casas; Catherine Toben; George Dedoussis; Joris Deelen; Peter Durda; Jorgen Engmann; Mary F Feitosa; Harald Grallert; Ann Hammarstedt; Sarah E Harris; Georg Homuth; Jouke-Jan Hottenga; Sirpa Jalkanen; Yalda Jamshidi; Magdalene C Jawahar; Tine Jess; Mika Kivimaki; Marcus E Kleber; Jari Lahti; Yongmei Liu; Pedro Marques-Vidal; Dan Mellström; Simon P Mooijaart; Martina Müller-Nurasyid; Brenda Penninx; Joana A Revez; Peter Rossing; Katri Räikkönen; Naveed Sattar; Hubert Scharnagl; Bengt Sennblad; Angela Silveira; Beate St Pourcain; Nicholas J Timpson; Julian Trollor; Jenny van Dongen; Diana Van Heemst; Sophie Visvikis-Siest; Peter Vollenweider; Uwe Völker; Melanie Waldenberger; Gonneke Willemsen; Delilah Zabaneh; Richard W Morris; Donna K Arnett; Bernhard T Baune; Dorret I Boomsma; Yen-Pei C Chang; Ian J Deary; Panos Deloukas; Johan G Eriksson; David M Evans; Manuel A Ferreira; Tom Gaunt; Vilmundur Gudnason; Anders Hamsten; Joachim Heinrich; Aroon Hingorani; Steve E Humphries; J Wouter Jukema; Wolfgang Koenig; Meena Kumari; Zoltan Kutalik; Deborah A Lawlor; Terho Lehtimäki; Winfried März; Karen A Mather; Silvia Naitza; Matthias Nauck; Claes Ohlsson; Jackie F Price; Olli Raitakari; Ken Rice; Perminder S Sachdev; Eline Slagboom; Thorkild I A Sørensen; Tim Spector; David Stacey; Maria G Stathopoulou; Toshiko Tanaka; S Goya Wannamethee; Peter Whincup; Jerome I Rotter; Abbas Dehghan; Eric Boerwinkle; Bruce M Psaty; Harold Snieder; Behrooz Z Alizadeh Journal: Hum Mol Genet Date: 2021-04-27 Impact factor: 6.150
Authors: Sarah Grosche; Ingo Marenholz; Jorge Esparza-Gordillo; Aleix Arnau-Soler; Erola Pairo-Castineira; Franz Rüschendorf; Tarunveer S Ahluwalia; Catarina Almqvist; Andreas Arnold; Hansjörg Baurecht; Hans Bisgaard; Klaus Bønnelykke; Sara J Brown; Mariona Bustamante; John A Curtin; Adnan Custovic; Shyamali C Dharmage; Ana Esplugues; Mario Falchi; Dietmar Fernandez-Orth; Manuel A R Ferreira; Andre Franke; Sascha Gerdes; Christian Gieger; Hakon Hakonarson; Patrick G Holt; Georg Homuth; Norbert Hubner; Pirro G Hysi; Marjo-Riitta Jarvelin; Robert Karlsson; Gerard H Koppelman; Susanne Lau; Manuel Lutz; Patrik K E Magnusson; Guy B Marks; Martina Müller-Nurasyid; Markus M Nöthen; Lavinia Paternoster; Craig E Pennell; Annette Peters; Konrad Rawlik; Colin F Robertson; Elke Rodriguez; Sylvain Sebert; Angela Simpson; Patrick M A Sleiman; Marie Standl; Dora Stölzl; Konstantin Strauch; Agnieszka Szwajda; Albert Tenesa; Philip J Thompson; Vilhelmina Ullemar; Alessia Visconti; Judith M Vonk; Carol A Wang; Stephan Weidinger; Matthias Wielscher; Catherine L Worth; Chen-Jian Xu; Young-Ae Lee Journal: Nat Commun Date: 2021-11-16 Impact factor: 14.919
Authors: Maria K Sobczyk; Tom G Richardson; Verena Zuber; Josine L Min; Tom R Gaunt; Lavinia Paternoster Journal: J Invest Dermatol Date: 2021-04-24 Impact factor: 8.551