Shared genetic variants suggest common pathways in allergy and autoimmune diseases

783 Pages·2017·15.83 MB·English

Accepted Manuscript
Shared genetic variants suggest common pathways in allergy and autoimmune
diseases
Eskil Kreiner, MD, PhD, Johannes Waage, PhD, Marie Standl, PhD, Susanne Brix,
PhD, Tune H. Pers, PhD, Alexessander Couto Alves, PhD, Nicole M. Warrington,
PhD, Carla MT. Tiesler, MSc, Elaine Fuertes, PhD, Lude Franke, PhD; AAGC, Joel N.
Hirschhorn, MD, PhD, Alan James, MD, Angela Simpson, MD, PhD, Joyce Y. Tung,
PhD, Gerard H. Koppelman, MD, PhD, Dirkje S. Postma, MD, PhD, Craig E. Pennell,
MD, PhD, Marjo-Riitta Jarvelin, MD, Adnan Custovic, MD, PhD, Nicholas Timpson,
PhD, Manuel A. Ferreira, PhD, David P. Strachan, MD, John Henderson, MD, David
Hinds, PhD, Hans Bisgaard, MD, DMSci, Klaus Bønnelykke, MD, PhD
PII: S0091-6749(17)30207-5
DOI: 10.1016/j.jaci.2016.10.055
Reference: YMAI 12620
To appear in: Journal of Allergy and Clinical Immunology
Received Date: 12 March 2016
Revised Date: 12 September 2016
Accepted Date: 11 October 2016
Please cite this article as: Kreiner E, Waage J, Standl M, Brix S, Pers TH, Couto Alves A, Warrington
NM, Tiesler CM, Fuertes E, Franke L, Hirschhorn JN, James A, Simpson A, Tung JY, Koppelman
GH, Postma DS, Pennell CE, Jarvelin M-R, Custovic A, Timpson N, Ferreira MA, Strachan DP,
Henderson J, Hinds D, Bisgaard H, Bønnelykke K, Shared genetic variants suggest common pathways
in allergy and autoimmune diseases, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/
j.jaci.2016.10.055.
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Shared genetic variants suggest common pathways in
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allergy and autoimmune diseases
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3 Eskil Kreiner, MD, PhD1,†; Johannes Waage, PhD1,†; Marie Standl, PhD2; Susanne
4 Brix, PhD3; Tune H Pers, PhD3-5; Alexessander Couto Alves, PhD6; NicoleP M
5 Warrington, PhD7,8; Carla MT Tiesler, MSc2,9; Elaine Fuertes, PhD2; Lude Franke,
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6 PhD10; AAGC, Joel N Hirschhorn, MD, PhD4,5,11; Alan James, MD12-1R4; Angela
7 Simpson, MD, PhD15; Joyce Y Tung, PhD16; Gerard H Koppelman, MD, PhD17;
8 Dirkje S Postma, MD, PhD18; Craig E Pennell, MD, PhD8; MarjoC-Riitta Jarvelin,
9 MD19-23; Adnan Custovic, MD, PhD24; Nicholas Timpson, PhD25; Manuel A
10 Ferreira, PhD26; David P Strachan, MD27; John Henderson,S MD28; David Hinds,
11 PhD16; Hans Bisgaard, MD, DMSci1; Klaus Bønnelykke, UMD, PhD1
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13 1: Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of
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14 Copenhagen, Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
15 2: Institute of Epidemiology I, Helmholtz Zentrum MünMchen, German Research Center for
16 Environmental Health, Neuherberg, Germany
17 3: Department of Biotechnology and Biomedicin e, Technical University of Denmark, Lyngby,
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18 Denmark
19 4: Division of Endocrinology and Center fEor Basic and Translational Obesity Research, Boston
20 Children's Hospital, Boston, USA
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21 5: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, USA
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22 6: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London,
23 UK
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24 7: The University of Queensland Diamantina Institute, The University of Queensland, Translational
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25 Research Institute, Brisbane, Australia
26 8: School of WomCen's and Infants' Health, The University of Western Australia, Perth, Australia
27 9: Ludwig-MaAximilians-University of Munich, Dr. von Hauner Children's Hospital, Munich, Germany
28 10: Department of Genetics, University of Groningen, University Medical Centre Groningen,
29 Groningen, 9711, The Netherlands
30 11: Department of Genetics, Harvard Medical School, Boston, 02115, USA
31 12: Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Western
32 Australia, Australia
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33 13: School of Medicine and Pharmacology, University of WA, Nedlands, Australia
34 14: Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute,
35 Nedlands, Australia
36 15: University of Manchester, Manchester Academic Health Science Centre, University Hospital of
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37 South Manchester NHS Foundation Trust, Manchester, UK
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38 16: 23andMe, Mountain View, Calif.
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39 17: Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital,
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40 GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
41 18: University of Groningen, Department of Pulmonology, GRIAC, University MCedical Center
42 Groningen, Groningen, The Netherlands
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43 19: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for
44 Environment and Health, School of Public Health, Imperial College London, UK
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45 20: Center for Life Course Epidemiology, Faculty of Medicine, P.O.Box 5000, FI-90014 University of
46 Oulu, Finland N
47 21: Biocenter Oulu, P.O.Box 5000, Aapistie 5A, FI-90014 UnAiversity of Oulu, Finland
48 22: Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O.Box 20, FI-90220 Oulu, 90029
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49 OYS, Finland
50 23: Department of Children and Young People a nd Families, National Institute for Health and
51 Welfare, Aapistie 1, Box 310, FI-90101 Oulu, FiDnland
52 24: University of Manchester, Manchester Academic Health Science Centre, University Hospital of
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53 South Manchester NHS Foundation Trust, Manchester, UK
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54 25: The MRC Integrative Epidemiology Unit at the University of Bristol, UK
55 26: Queensland Institute of MedPical Research, Brisbane, Australia
56 27: Population Health ReseEarch Institute, St George's, University of London, Cranmer Terrace,
57 London SW17 0RE
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58 28: School of Social and Community Medicine, University of Bristol, Bristol, UK
59 †: These authors cContributed equally to this work.
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61 Corresponding author:
62 Klaus Bønnelykke, MD, PhD
63 Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of
64 Copenhagen, Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte,
65 Denmark
66 Email: [email protected]
67 Phone: [phone]
68 Fax: [phone]
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69 Abstract
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71 Background
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72 The relationship between allergy and autoimmune disorders is complex and poorly
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73 understood.
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75 Objective C
76 To investigate commonalities in genetic loci and pathways betweenS allergy and autoimmune
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77 diseases to elucidate shared disease mechanisms.
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79 Methods
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80 We meta-analyzed two GWAS on self-reported allergy and sensitization comprising a total of
81 62,330 individuals. These results were used to calculate enrichment for SNPs previously
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82 associated with autoimmune diseases. Furthermore, we probed for enrichment within
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83 genetic pathways and of transcription factor binding sites, and characterized commonalities
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84 in the variant burden on tissue-specific regulatory sites by calculating the enrichment of
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85 allergy SNPs falling in genEe regulatory regions in various cells using Encode Roadmap DHS
86 data, and compared Cthe allergy data with all known diseases.
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88 Results A
89 Among 290 loci previously associated with 16 autoimmune diseases, we found a significant
90 enrichment of loci also associated with allergy (p=1.4e-17) encompassing 29 loci at a false
91 discovery rate<0.05. Such enrichment seemed to be a general characteristic for all
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92 autoimmune diseases. Among the common loci, 48% had the same direction of effect for
93 allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs
94 falling within immune pathways and regions of chromatin accessible in immune cells that
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95 was also represented in autoimmune diseases, but not in other diseases.
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97 Conclusion
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98 We identified shared susceptibility loci and commonalities in pathways between allergy and
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99 autoimmune diseases, suggesting shared diseases mechanisms. Further studies of these
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100 shared genetic mechanisms might help understanding the complex relationship between
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101 these diseases, including the parallel increase in disease prevalence.
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103 Capsule Summary
104 We identified shared susceptibility loci and commonalities in pathways between allergy and
105 autoimmune diseases. Further studies of these loci and related mechanisms might helpT
106 understanding the complex relationship between allergy and autoimmunity. P
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108 Key messages C
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109 - Allergy and autoimmune diseases share genetic susceptibility loci.
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110 - These results indicate commonalities in gene regulation and genetic pathways
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111 between allergy and autoimmune diseases.
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112 - Further studies of common genetic loci and the related mechanisms might help
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113 understanding the complex relationship between allergy and autoimmunity.

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116 Key words
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117 Allergy, Single Nucleotide Polymorphism, Autoimmune Disease, Autoimmunity, Genetic
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118 Association Studies
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120 Abbreviations
121 DEPICT: Data-driven Expression Prioritized Integration for Complex Traits gene set
122 enrichment method
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123 DHS: DNase Hypersensitive Sites
124 GWA(S): Genome Wide Association (Studies)
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125 PCA: Principal Component Analysis
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126 SNP: Single Nucleotide Polymorphism
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128 Introduction
129 There has been a parallel increase in allergic and autoimmune disorders in recent decades in
130 “westernized” countries1 suggesting that these diseases may share disease mechanismTs and
131 etiologies. In line with this, allergy and autoimmune disorders seem to share envirPonmental
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132 risk factors including birth by caesarian section2. This observation is in apparent contrast to
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133 the understanding of allergy and autoimmune diseases as representatives of distinct
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134 immunological disorders with counteracting underlying immune mechanisms. Autoimmune
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135 diseases are in general thought to act through a Th1/Th17-driveUn cell mediated immune
136 response,3 while allergy and asthma encompass a Th2-medNiated response4. Counteracting
137 immune mechanisms have been supported by some eApidemiological studies of comorbidity
138 suggesting a lower incidence of allergy among patMients with autoimmune diseases, including
139 rheumatoid arthritis5,6 and multiples scleros is7, although the evidence of such inverse
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140 relationship is conflicting.8
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141 Both allergy and autoimmune diseases are highly heritable diseases and an increasing
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142 number of susceptibility loci have been discovered.9–11 We hypothesized that studying
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143 commonalities in the genetic architecture could provide a key to understanding the complex
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144 relationship between these diseases by pinpointing possible common disease mechanisms.
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145 In a wider perspective, this might help to explain the mechanisms and aetiologies
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146 responsible Afor the contemporaneous, dramatic increase in incidence of allergic and
147 autoimmune disorders1.
148 We studied commonalities between allergy and autoimmune disease in terms of
149 susceptibility loci, genetic pathways and regulatory mechanisms. We meta-analyzed two
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150 GWAS on allergic sensitization and allergic symptoms representing the largest GWAS on
151 allergy to date. These data were then combined with publically available GWAS data on
152 autoimmune diseases, as well as public data on molecular pathways, transcription factor
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153 binding sites and regulatory DNA regions. The primary analyses used a methodological
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154 approach that was agnostic to the direction of effect (including loci where the risk-allele was
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155 the same for allergy and autoimmune disease as well as loci where the risk allele for one
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156 disease was protective for the other). We hypothesized that loci with same direction of
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157 effect for different diseases might be involved in shared mechanisms and thereby help
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158 understanding the parallel epidemics of diseases, while loci with opposite direction of effect
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159 might help understanding counteracting (diverging) disease mechanisms. In analogue, gene
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160 variants in beta-adrenoreceptors are likely to showM diverging effects with respect to risk of
161 cardiac and respiratory diseases but still pinpoint an essential mechanism for both diseases.

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162 For allergy and autoimmune diseases such loci might be involved in “polarization” of the
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163 immune response. We therefore chose an approach that would capture common genetic
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164 loci with both same and opposite direction of effect since we believe that both might confer
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165 important information and thereby help to elucidate the complex mechanistic relationship
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166 between these diseases.
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