Eskil Kreiner1, Johannes Waage1, Marie Standl2, Susanne Brix3, Tune H Pers4, Alexessander Couto Alves5, Nicole M Warrington6, Carla M T Tiesler7, Elaine Fuertes2, Lude Franke8, Joel N Hirschhorn9, Alan James10, Angela Simpson11, Joyce Y Tung12, Gerard H Koppelman13, Dirkje S Postma14, Craig E Pennell15, Marjo-Riitta Jarvelin16, Adnan Custovic11, Nicholas Timpson17, Manuel A Ferreira18, David P Strachan19, John Henderson20, David Hinds12, Hans Bisgaard21, Klaus Bønnelykke1. 1. COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. 2. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 3. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. 4. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Mass; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Mass; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. 5. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. 6. University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia; School of Women's and Infants' Health, University of Western Australia, Perth, Australia. 7. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Ludwig-Maximilians-Universität of Munich, Dr. von Hauner Children's Hospital, Munich, Germany. 8. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 9. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Mass; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Mass; Department of Genetics, Harvard Medical School, Boston, Mass. 10. Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia; School of Medicine and Pharmacology, University of West Australia, Nedlands, Australia; Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Australia. 11. University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom. 12. 23andMe, Mountain View, Calif. 13. University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands. 14. University of Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, Groningen, The Netherlands. 15. School of Women's and Infants' Health, University of Western Australia, Perth, Australia. 16. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland. 17. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom. 18. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 19. Population Health Research Institute, St George's, University of London, London, United Kingdom. 20. School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom. 21. COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.
Abstract
BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
Authors: Johannes Waage; Marie Standl; John A Curtin; Leon E Jessen; Jonathan Thorsen; Chao Tian; Nathan Schoettler; Carlos Flores; Abdel Abdellaoui; Tarunveer S Ahluwalia; Alexessander C Alves; Andre F S Amaral; Josep M Antó; Andreas Arnold; Amalia Barreto-Luis; Hansjörg Baurecht; Catharina E M van Beijsterveldt; Eugene R Bleecker; Sílvia Bonàs-Guarch; Dorret I Boomsma; Susanne Brix; Supinda Bunyavanich; Esteban G Burchard; Zhanghua Chen; Ivan Curjuric; Adnan Custovic; Herman T den Dekker; Shyamali C Dharmage; Julia Dmitrieva; Liesbeth Duijts; Markus J Ege; W James Gauderman; Michel Georges; Christian Gieger; Frank Gilliland; Raquel Granell; Hongsheng Gui; Torben Hansen; Joachim Heinrich; John Henderson; Natalia Hernandez-Pacheco; Patrick Holt; Medea Imboden; Vincent W V Jaddoe; Marjo-Riitta Jarvelin; Deborah L Jarvis; Kamilla K Jensen; Ingileif Jónsdóttir; Michael Kabesch; Jaakko Kaprio; Ashish Kumar; Young-Ae Lee; Albert M Levin; Xingnan Li; Fabian Lorenzo-Diaz; Erik Melén; Josep M Mercader; Deborah A Meyers; Rachel Myers; Dan L Nicolae; Ellen A Nohr; Teemu Palviainen; Lavinia Paternoster; Craig E Pennell; Göran Pershagen; Maria Pino-Yanes; Nicole M Probst-Hensch; Franz Rüschendorf; Angela Simpson; Kari Stefansson; Jordi Sunyer; Gardar Sveinbjornsson; Elisabeth Thiering; Philip J Thompson; Maties Torrent; David Torrents; Joyce Y Tung; Carol A Wang; Stephan Weidinger; Scott Weiss; Gonneke Willemsen; L Keoki Williams; Carole Ober; David A Hinds; Manuel A Ferreira; Hans Bisgaard; David P Strachan; Klaus Bønnelykke Journal: Nat Genet Date: 2018-07-16 Impact factor: 38.330
Authors: Michelle M Stein; Emma E Thompson; Nathan Schoettler; Britney A Helling; Kevin M Magnaye; Catherine Stanhope; Catherine Igartua; Andréanne Morin; Charles Washington; Dan Nicolae; Klaus Bønnelykke; Carole Ober Journal: J Allergy Clin Immunol Date: 2018-01-04 Impact factor: 10.793