Meta-analysis identifies seven susceptibility loci involved in the atopic march

Ingo Marenholz; Jorge Esparza-Gordillo; Franz Rüschendorf; Anja Bauerfeind; David P Strachan; Ben D Spycher; Hansjörg Baurecht; Patricia Margaritte-Jeannin; Annika Sääf; Marjan Kerkhof; Markus Ege; Svetlana Baltic; Melanie C Matheson; Jin Li; Sven Michel; Wei Q Ang; Wendy McArdle; Andreas Arnold; Georg Homuth; Florence Demenais; Emmanuelle Bouzigon; Cilla Söderhäll; Göran Pershagen; Johan C de Jongste; Dirkje S Postma; Charlotte Braun-Fahrländer; Elisabeth Horak; Ludmila M Ogorodova; Valery P Puzyrev; Elena Yu Bragina; Thomas J Hudson; Charles Morin; David L Duffy; Guy B Marks; Colin F Robertson; Grant W Montgomery; Bill Musk; Philip J Thompson; Nicholas G Martin; Alan James; Patrick Sleiman; Elina Toskala; Elke Rodriguez; Regina Fölster-Holst; Andre Franke; Wolfgang Lieb; Christian Gieger; Andrea Heinzmann; Ernst Rietschel; Thomas Keil; Sven Cichon; Markus M Nöthen; Craig E Pennell; Peter D Sly; Carsten O Schmidt; Anja Matanovic; Valentin Schneider; Matthias Heinig; Norbert Hübner; Patrick G Holt; Susanne Lau; Michael Kabesch; Stefan Weidinger; Hakon Hakonarson; Manuel A R Ferreira; Catherine Laprise; Maxim B Freidin; Jon Genuneit; Gerard H Koppelman; Erik Melén; Marie-Hélène Dizier; A John Henderson; Young Ae Lee

doi:10.1038/ncomms9804

Meta-analysis identifies seven susceptibility loci involved in the atopic march

Nat Commun. 2015 Nov 6:6:8804. doi: 10.1038/ncomms9804.

Authors

Ingo Marenholz^{1

2}, Jorge Esparza-Gordillo^{1

2}, Franz Rüschendorf¹, Anja Bauerfeind¹, David P Strachan³, Ben D Spycher⁴, Hansjörg Baurecht⁵, Patricia Margaritte-Jeannin^{6

7}, Annika Sääf⁸, Marjan Kerkhof⁹, Markus Ege¹⁰, Svetlana Baltic¹¹, Melanie C Matheson¹², Jin Li¹³, Sven Michel¹⁴, Wei Q Ang¹⁵, Wendy McArdle¹⁶, Andreas Arnold¹⁷, Georg Homuth¹⁸, Florence Demenais^{6

7}, Emmanuelle Bouzigon^{6

7}, Cilla Söderhäll¹⁹, Göran Pershagen⁸, Johan C de Jongste²⁰, Dirkje S Postma²¹, Charlotte Braun-Fahrländer²², Elisabeth Horak²³, Ludmila M Ogorodova²⁴, Valery P Puzyrev^{24

25}, Elena Yu Bragina²⁵, Thomas J Hudson²⁶, Charles Morin²⁷, David L Duffy²⁸, Guy B Marks²⁹, Colin F Robertson³⁰, Grant W Montgomery²⁸, Bill Musk³¹, Philip J Thompson¹¹, Nicholas G Martin²⁸, Alan James³¹, Patrick Sleiman^{13

32}, Elina Toskala³³, Elke Rodriguez⁵, Regina Fölster-Holst⁵, Andre Franke³⁴, Wolfgang Lieb³⁵, Christian Gieger³⁶, Andrea Heinzmann³⁷, Ernst Rietschel³⁸, Thomas Keil^{39

40}, Sven Cichon^{41

42

43

44}, Markus M Nöthen^{41

42}, Craig E Pennell¹⁵, Peter D Sly⁴⁵, Carsten O Schmidt⁴⁶, Anja Matanovic^{1

2}, Valentin Schneider¹, Matthias Heinig^{1

47}, Norbert Hübner¹, Patrick G Holt^{45

48}, Susanne Lau⁴⁹, Michael Kabesch¹⁴, Stefan Weidinger⁵, Hakon Hakonarson^{13

32}, Manuel A R Ferreira²⁸, Catherine Laprise⁵⁰, Maxim B Freidin²⁵, Jon Genuneit⁵¹, Gerard H Koppelman⁵², Erik Melén^{8

53}, Marie-Hélène Dizier^{6

7}, A John Henderson¹⁶, Young Ae Lee^{1

2}

Affiliations

¹ Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.
² Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.
³ Population Health Research Institute, St George's, University of London, London, UK.
⁴ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁵ Department of Dermatology, Allergology, and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁶ Inserm, UMR-946, F-75010 Paris, France.
⁷ Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007 Paris, France.
⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁹ University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
¹⁰ Dr von Hauner Children's Hospital, Ludwig Maximilians University Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.
¹¹ Lung Institute of Western Australia, University of Western Australia, Perth, Western Australia, Australia.
¹² Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia.
¹³ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Pediatric Pneumology and Allergy, University Children`s Hospital Regensburg (KUNO), Regensburg, Germany.
¹⁵ School of Women and Infant's Health, University of Western Australia, Perth, Western Australia, Australia.
¹⁶ School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹⁷ Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany.
¹⁸ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
¹⁹ Department of Biosciences and Nutrition, and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Pediatrics, Pediatric Chest Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
²¹ Department of Pulmonology and GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²² Swiss Tropical and Public Health Institute and the University of Basel, Basel, Switzerland.
²³ Division of Pediatric Cardiology and Pulmonology, Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria.
²⁴ Siberian State Medical University, Tomsk, Russia.
²⁵ Research Institute of Medical Genetics, Tomsk, Russia.
²⁶ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
²⁷ Centre de santé et de services sociaux de Chicoutimi, Saguenay, Québec, Canada.
²⁸ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁹ Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
³⁰ Department of Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
³¹ Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
³² Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³³ Department of Otolaryngology-Head and Neck Surgery, Temple University, School of Medicine, Philadelphia, Pennsylvania, USA.
³⁴ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
³⁵ Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
³⁶ Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
³⁷ University Children's Hospital, Albert Ludwigs University, Freiburg, Germany.
³⁸ University Children's Hospital, University of Cologne, Cologne, Germany.
³⁹ Institute of Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany.
⁴⁰ Institute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.
⁴¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁴² Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
⁴³ Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
⁴⁴ Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Jülich, Jülich, Germany.
⁴⁵ Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Queensland, Australia.
⁴⁶ Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Max Planck Institute for Molecular Genetics, Berlin, Germany.
⁴⁸ Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
⁴⁹ Department of Pediatric Pneumology and Immunology, Charité University Medical Center, Berlin, Germany.
⁵⁰ Université du Québec à Chicoutimi, Saguenay, Québec, Canada.
⁵¹ Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
⁵² Department of Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital and GRIAC Research Institute, Groningen, The Netherlands.
⁵³ Sachs' Children's Hospital, Stockholm, Sweden.

Abstract

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Publication types

Meta-Analysis

MeSH terms

Adaptor Proteins, Vesicular Transport / genetics
Adolescent
Adult
Amino Acid Transport Systems, Neutral / genetics
Asthma / genetics*
Calcium-Binding Proteins / genetics
Carrier Proteins / genetics
Child
Child, Preschool
DNA-Binding Proteins / genetics
Dermatitis, Atopic / genetics*
Disease Progression
Female
Filaggrin Proteins
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Ikaros Transcription Factor / genetics
Interleukin-4 / genetics
Kinesins / genetics
Logistic Models
Male
Membrane Proteins / genetics
Middle Aged
Neoplasm Proteins / genetics
Nerve Tissue Proteins / genetics
Nuclear Proteins / genetics
Phenotype
Polymorphism, Single Nucleotide
Receptor, Fibroblast Growth Factor, Type 1 / genetics
Repressor Proteins / genetics
Transcription Factors / genetics
Young Adult

Substances

AP5B1 protein, human
Adaptor Proteins, Vesicular Transport
Amino Acid Transport Systems, Neutral
Calcium-Binding Proteins
Carrier Proteins
DNA-Binding Proteins
EFHC1 protein, human
EMSY protein, human
FLG protein, human
Filaggrin Proteins
IKZF3 protein, human
IL4 protein, human
KIF3A protein, human
LRRC32 protein, human
Membrane Proteins
Neoplasm Proteins
Nerve Tissue Proteins
Nuclear Proteins
OVOL1 protein, human
Repressor Proteins
SLC6A15 protein, human
TMTC2 protein, human
Transcription Factors
Ikaros Transcription Factor
Interleukin-4
FGFR1 protein, human
Receptor, Fibroblast Growth Factor, Type 1
Kinesins

Abstract

Publication types

MeSH terms

Substances

Grants and funding