Shared genetic variants suggest common pathways in allergy and autoimmune diseases - 06/09/17

Doi : 10.1016/j.jaci.2016.10.055

Eskil Kreiner, MD, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Johannes Waage, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Marie Standl, PhD ^b, Susanne Brix, PhD ^c, Tune H. Pers, PhD ^c,^d,^e,^cc, Alexessander Couto Alves, PhD ^f, Nicole M. Warrington, PhD ^g,^h, Carla M.T. Tiesler, MSc ^b,ⁱ, Elaine Fuertes, PhD ^b, Lude Franke, PhD ^j, Joel N. Hirschhorn, MD, PhD ^d,^e,^k, Alan James, MD ^l,^m,ⁿ, Angela Simpson, MD, PhD ^o, Joyce Y. Tung, PhD ^p, Gerard H. Koppelman, MD, PhD ^q, Dirkje S. Postma, MD, PhD ^r, Craig E. Pennell, MD, PhD ^h, Marjo-Riitta Jarvelin, MD ^s,^t,^u,^v,^w, Adnan Custovic, MD, PhD ^x, Nicholas Timpson, PhD ^y, Manuel A. Ferreira, PhD ^z, David P. Strachan, MD ^aa, John Henderson, MD ^bb, David Hinds, PhD ^p, Hans Bisgaard, MD, DMSc ^a,^⁎ , Klaus Bønnelykke, MD, PhD ^a
^a COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
^b Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^c The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
^d Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Mass
^e Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Mass
^f Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
^g University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
^h School of Women's and Infants' Health, University of Western Australia, Perth, Australia
ⁱ Ludwig-Maximilians-Universität of Munich, Dr. von Hauner Children's Hospital, Munich, Germany
^j Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
^k Department of Genetics, Harvard Medical School, Boston, Mass
^l Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia
^m School of Medicine and Pharmacology, University of West Australia, Nedlands, Australia
ⁿ Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Australia
^o University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
^p 23andMe, Mountain View, Calif
^q University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands
^r University of Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, Groningen, The Netherlands
^s 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
^t Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland
^u Biocenter Oulu, University of Oulu, Oulu, Finland
^v Unit of Primary Care, Oulu University Hospital, Oulu, Finland
^w Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland
^x University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
^y MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
^bb School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
^z QIMR Berghofer Medical Research Institute, Brisbane, Australia
^aa Population Health Research Institute, St George's, University of London, London, United Kingdom
^cc Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

^∗Corresponding author: Hans Bisgaard, MD, DMSc, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.COPSAC, Copenhagen Prospective Studies on Asthma in ChildhoodHerlev and Gentofte HospitalUniversity of CopenhagenCopenhagenDenmark

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.

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Graphical abstract

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Key words : Allergy, single nucleotide polymorphism, autoimmune disease, autoimmunity, genetic association studies

Abbreviations used : DEPICT, DHS, GWAS, PCA, SNP, Treg

Plan

Methods

Study group

Common genetic loci

Commonalities in genetic pathways

Common disease-implicated cell types

Results

Allergy meta-analysis

Commonalities in genetic loci, pathways, and disease-implicated cell types between allergy and autoimmune diseases

Specific common genetic loci

Shared and differential genetic pathways for allergy and Crohn disease

Discussion

Strengths and limitations

Interpretation

Disclosure of potential conflict of interest: E. Kreiner is employed at Novo Nordisk A/S. A. Simpson has received a grant from the Medical Research Council. J. Y. Tung is employed by and receives stock/stock options from 23andMe. G. H. Koppelman has received grants from the Netherlands Lung Foundation, Stichting Astma Bestrijding, Ubbo Emmius Foundation, and TEVA, The Netherlands. D. S. Postma has consultant arrangements with Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and TEVA and has received grants from AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, and Roche. C. E. Pennell has received grants from the National Health Medical Research Council, Telethon, and Telethon-Perth Children's Hospital Research Fund; is employed by the University of Western Australia; and has received travel support for invited presentations from Raine Study Core Funds, Haematology Association of Australia, Global Obstetric Update, March of Dimes and Burrows Wellcome. A. Custovic has received personal fees from Novartis, Regeneron/Sanofi, ALK-Abelló, Bayer, and Thermo Fisher. M. A. Ferreira has received a grant from the National Health Medical Research Council of Australia (Project Grant 613627). J. Henderson has received grants from the Medical Research Council, Wellcome, and 23andMe. D. Hinds has received a grant from the National Heart, Lung, and Blood Institute (grant 1R43HL115873-01) and is employed by and has received stock/stock options from 23andMe. H. Bisgaard has received grants from the Danish Ministry of Health, the Lundbeck Foundation, and the Danish Strategic Research Foundation and has consultant arrangements with Chiesi Pharmaceuticals and Boehringer Ingelheim. K. Bønnelykke has received grants from the Danish Ministry of Health, the Lundbeck Foundation, and the Danish Strategic Research Foundation. The rest of the authors declare that they have no relevant conflicts of interest.

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Shared genetic variants suggest common pathways in allergy and autoimmune diseases - 06/09/17

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

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