Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology
Authors: Sarah Grosche
AAGC collaborators
Christian Gieger
Kimberley Burrows
Jonathan Beesley
Jonas B Nielsen
Quinta Helmer
Chris W Medway
Melanie C Matheson
Mari L√∏set
Konstantin Strauch
Dorret I Boomsma
Elke Rodr√≠guez
Vilhelmina Ullemar
Melanie Hotze
Oliver Hummel
Jouke-Jan Hottenga
Yi Lu
Robert Karlsson
Shyamali C Dharmage
Judith M Vonk
Jorge Esparza-Gordillo
Cristen J Willer
Catarina Almqvist
Stefan Karrasch
Joshua D Hoffman
Hansj√∂rg Baurecht
Edward Mountjoy
Wei Zhou
Lavinia Paternoster
Eric Jorgenson
Manuel A Ferreira
Ronald B Melles
Oddgeir L Holmen
Arnulf Langhammer
Ben M Brumpton
LifeLines Cohort Study
John S Witte
Gon√ßalo R Abecasis
BIOS consortium
Philip J Thompson
Rick Jansen
Andreas Arnold
Natalija Novak
Norbert H√ºbner
Franz R√ºschendorf
Jenny van Dongen
David L Duffy
Stephan Weidinger
Lars G Fritsche
Kristian Hveem
Nicholas G Martin
Lisa M Bain
Joana A Revez
David A Hinds
Ingo Marenholz
Holger Schulz
Chao Tian
Young-Ae Lee
Jie Zheng
Georg Homuth
23andMe Research Team
Annika Tillander
Maiken E Gabrielsen
Gerard H Koppelman
Carsten O Schmidt
Gonneke Willemsen
Andre Franke
Patrik K E Magnusson
Brunilda Balliu
Journal: Nature Genetics (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Asthma; hay fever; eczema; allergic disease; genome-wide association study
Affiliations: Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Epidemiology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands., Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Max Delbr√ºck Center (MDC) for Molecular Medicine, Berlin, Germany., Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charit√© Universit√§tsmedizin Berlin and Max Delbr√ºck Center, Berlin, Germany., Research, 23andMe, Mountain View, California, USA., Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA., Department of Biological Psychology, Netherlands Twin Register, Vrije University, Amsterdam, the Netherlands., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK., K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA., Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany., Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia., Department of Pathology, Stanford University School of Medicine, Stanford, California, USA., Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA., Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Department of Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA., Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany., Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany., Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany., Institute for Respiratory Health, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia., Department of Dermatology and Allergology, University Hospital Bonn, Bonn, Germany., Institute of Epidemiology I, Helmholtz Zentrum M√ºnchen-German Research Center for Environmental Health, Neuherberg, Germany., Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany., Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universit√§t, Munich, Germany., Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum M√ºnchen-German Research Center for Environmental Health, Neuherberg, Germany., Institute of Genetic Epidemiology, Helmholtz Zentrum M√ºnchen-German Research Center for Environmental Health, Neuherberg, Germany., Division of Research, Kaiser Permanente Northern California, Oakland, California, USA., Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands., Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden., University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Pediatric Pulmonology and Pediatric Allergology, and University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.

Abstract:  Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P &lt; 3 √ó 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes. 

Retracted: No

PubPeer comments:
 (the [following comment ] has been rejected by nature genetics) The era of modern allergy genetics started in 1997 with the Transatlantic Airway Conference at Key Biscayne, Florida. 20 years later, the paper of Ferreira et al. (1) marks the end of an era by reporting the largest study so far of asthma, u201ehay feveru201c and atopic eczema in 180,000 cases. It is the result of an huge international effort of many named and unnamed scientists. Unfortunately, there are major impairments regarding scope of analysis, epidemiological and bioinformatics methods, interpretation and data release. Some issues even contradict nature genetics editorial policies (2), (3), (4). Although the article title promises to show the shared genetic origin of asthma, hay fever (a lay term that should be avoided as misnomer) and atopic eczema, the answer remains elusive as only results of a pair-wise case-only association are given. For a shared genetic origin, the result of case-control associations for the possible intersections of the traits would need to be compared. Having more individuals under study means of course that more regions will be discovered (5) than in earlier studies. Bigger, however, does not always mean better, if phenotypes are poorly defined. The online questionnaire of 23andme customers (6) has never been validated with clinical data although being used now in a multi-national, multi-ethnic and multi-language setting. Only a rudimentary baseline description has been released (7) while even results reported in this paper are not public available. More questions are being raised as UK Biobank is contributing most controls but US based 23andme most cases. One third of the studies used case ascertainment while the heterogeneity between studies is not discussed although the addition of 23andme samples does not only inflate but also removes association peaks (as an example see Supplement Figure 15, peak after region 83). The interpretation of known or unknown region as presented in Figure 1 of the Ferreira et al. paper is misleading as several studies already contributed results to the GWAS catalogue that is used as a reference here. In some regions, the results are therefore just repetitions of earlier findings (Supplement Figure 57). The authors would also need to show for each of their new association that these are not just chance findings (Supplement Figure 2, region 13). Unfortunately Ferreira is agnostic about 800 articles (8) including numerous high ranked articles from the pre-GWAS era (9-17). Many of these associations have been replicated more than 5 times (18). Even the strongest association in the online data supplement (Figure 36, region #14, IL1R1) has already been described in the pre-GWAS era (19). Why do the authors not even cite their own related work (20)? Why do they not mention another paper of the UK biobank that has nearly the same title (21)? Why do co-authors of the new paper publish in parallel an even larger study with another allergy protective SNP that is not reported here (22)? The genes presented in table 1 are positional candidates being in the vicinity of a disease associated SNP. Just by eye-balling the partitioning of the region is not always optimal in particular where many sentinel SNPs had to be placed in one region. Regions are highly different with regard to gene content, SNP coverage, minor allele frequency and linkage disequilibrium (and therefore also the power to detect an association may vary). Unfortunately strong and robust associations are being treated equally along with only borderline significant associations when fed into a bioinformatics pipeline. The outcome is somewhat trivial in the light of many experimental studies in the field. Producing a list of u201edruggableu201c genes from some u201esentinelu201c SNPs is an in silico overprediction based on the assumed function of nearby genes. It misses the fact that there are real-life GWAS outcomes (23) that are already being tested in phase II studies like AMG 282, an IL33 antibody. In conclusion, having now seen the largest study so far of allergy genetics, we are set back to the Transatlantic Airway Conference 1997 where the first positional candidate gene was announced by Slutsky and Zamel, reportedly a u201escientific result without scienceu201c (24). References 1. Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, et al. 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