Meta-Analysis

. 2018 Jan;50(1):42-53.

doi: 10.1038/s41588-017-0014-7. Epub 2017 Dec 22.

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Florence Demenais^#^{1

2}, Patricia Margaritte-Jeannin^#^{3

4}, Kathleen C Barnes^#⁵, William O C Cookson^#⁶, Janine Altmüller⁷, Wei Ang⁸, R Graham Barr⁹, Terri H Beaty¹⁰, Allan B Becker¹¹, John Beilby¹², Hans Bisgaard¹³, Unnur Steina Bjornsdottir¹⁴, Eugene Bleecker¹⁵, Klaus Bønnelykke¹³, Dorret I Boomsma¹⁶, Emmanuelle Bouzigon^{3

4}, Christopher E Brightling¹⁷, Myriam Brossard^{3

4}, Guy G Brusselle^{18

19

20}, Esteban Burchard²¹, Kristin M Burkart²², Andrew Bush^{23

24}, Moira Chan-Yeung²⁵, Kian Fan Chung^{23

26}, Alexessander Couto Alves²⁷, John A Curtin²⁸, Adnan Custovic²⁹, Denise Daley^{25

30}, Johan C de Jongste³¹, Blanca E Del-Rio-Navarro³², Kathleen M Donohue⁹, Liesbeth Duijts³³, Celeste Eng³⁴, Johan G Eriksson³⁵, Martin Farrall^{36

37}, Yuliya Fedorova³⁸, Bjarke Feenstra³⁹, Manuel A Ferreira⁴⁰; Australian Asthma Genetics Consortium (AAGC) collaborators; Maxim B Freidin⁴¹, Zofia Gajdos^{42

43}, Jim Gauderman⁴⁴, Ulrike Gehring⁴⁵, Frank Geller³⁹, Jon Genuneit⁴⁶, Sina A Gharib⁴⁷, Frank Gilliland⁴⁴, Raquel Granell^{48

49}, Penelope E Graves⁵⁰, Daniel F Gudbjartsson^{51

52}, Tari Haahtela⁵³, Susan R Heckbert⁵⁴, Dick Heederik⁴⁵, Joachim Heinrich^{55

56}, Markku Heliövaara⁵⁷, John Henderson^{48

49}, Blanca E Himes⁵⁸, Hiroshi Hirose⁵⁹, Joel N Hirschhorn^{43

60

61}, Albert Hofman^{19

62}, Patrick Holt⁶³, Jouke Hottenga¹⁶, Thomas J Hudson^{64

65}, Jennie Hui^{12

66

67}, Medea Imboden^{68

69}, Vladimir Ivanov⁷⁰, Vincent W V Jaddoe⁷¹, Alan James^{72

73}, Christer Janson⁷⁴, Marjo-Riitta Jarvelin^{75

76

77

78}, Deborah Jarvis^{23

79}, Graham Jones⁸⁰, Ingileif Jonsdottir^{51

81}, Pekka Jousilahti⁵⁷, Michael Kabesch⁸², Mika Kähönen⁸³, David B Kantor^{84

85}, Alexandra S Karunas^{38

86}, Elza Khusnutdinova^{38

86}, Gerard H Koppelman^{87

88}, Anita L Kozyrskyj⁸⁹, Eskil Kreiner¹³, Michiaki Kubo⁹⁰, Rajesh Kumar^{91

92}, Ashish Kumar^{68

69

93}, Mikko Kuokkanen^{57

94}, Lies Lahousse^{19

95}, Tarja Laitinen⁹⁶, Catherine Laprise^{97

98}, Mark Lathrop⁹⁹, Susanne Lau¹⁰⁰, Young-Ae Lee^{101

102}, Terho Lehtimäki¹⁰³, Sébastien Letort^{3

4}, Albert M Levin¹⁰⁴, Guo Li⁴⁷, Liming Liang^{62

105}, Laura R Loehr¹⁰⁶, Stephanie J London¹⁰⁷, Daan W Loth¹⁹, Ani Manichaikul¹⁰⁸, Ingo Marenholz^{101

102}, Fernando J Martinez⁵⁰, Melanie C Matheson¹⁰⁹, Rasika A Mathias¹¹⁰, Kenji Matsumoto¹¹¹, Hamdi Mbarek¹⁶, Wendy L McArdle¹¹², Mads Melbye^{39

113

114}, Erik Melén^{93

115

116}, Deborah Meyers¹⁵, Sven Michel⁸², Hamida Mohamdi^{3

4}, Arthur W Musk^{117

118}, Rachel A Myers¹¹⁹, Maartje A E Nieuwenhuis^{88

120}, Emiko Noguchi¹²¹, George T O'Connor^{122

123}, Ludmila M Ogorodova¹²⁴, Cameron D Palmer^{43

60}, Aarno Palotie^{94

125

126}, Julie E Park²⁵, Craig E Pennell⁸, Göran Pershagen^{93

115}, Alexey Polonikov⁷⁰, Dirkje S Postma^{88

120}, Nicole Probst-Hensch^{68

69}, Valery P Puzyrev⁴¹, Benjamin A Raby¹²⁷, Olli T Raitakari¹²⁸, Adaikalavan Ramasamy^{27

129}, Stephen S Rich¹⁰⁸, Colin F Robertson¹³⁰, Isabelle Romieu^{131

132}, Muhammad T Salam^{44

133}, Veikko Salomaa⁵⁷, Vivi Schlünssen¹³⁴, Robert Scott¹³⁵, Polina A Selivanova¹³⁶, Torben Sigsgaard¹³⁴, Angela Simpson^{28

137}, Valérie Siroux^{138

139}, Lewis J Smith¹⁴⁰, Maria Solodilova⁷⁰, Marie Standl⁵⁶, Kari Stefansson^{51

81}, David P Strachan¹⁴¹, Bruno H Stricker^{19

142

143}, Atsushi Takahashi⁹⁰, Philip J Thompson¹⁴⁴, Gudmar Thorleifsson⁵¹, Unnur Thorsteinsdottir^{51

81}, Carla M T Tiesler^{56

145}, Dara G Torgerson³⁴, Tatsuhiko Tsunoda^{90

146}, André G Uitterlinden¹⁴³, Ralf J P van der Valk¹⁴⁷, Amaury Vaysse^{3

4}, Sailaja Vedantam^{42

43}, Andrea von Berg¹⁴⁸, Erika von Mutius^{149

150}, Judith M Vonk^{88

151}, Johannes Waage¹³, Nick J Wareham¹³⁵, Scott T Weiss¹²⁷, Wendy B White¹⁵², Magnus Wickman^{93

153}, Elisabeth Widén⁹⁴, Gonneke Willemsen¹⁶, L Keoki Williams^{154

155}, Inge M Wouters⁴⁵, James J Yang¹⁵⁶, Jing Hua Zhao¹³⁵, Miriam F Moffatt⁶, Carole Ober¹⁵⁷, Dan L Nicolae¹⁵⁸

Affiliations

¹ Genetic Variation and Human Diseases Unit (UMR-946), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. florence.demenais@inserm.fr.
² Institut Universitaire d'Hématologie, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France. florence.demenais@inserm.fr.
³ Genetic Variation and Human Diseases Unit (UMR-946), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
⁴ Institut Universitaire d'Hématologie, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France.
⁵ Division of Biomedical Informatics and Personalized Medicine, Colorado Center for Personalized Medicine, University of Colorado, Denver, CO, USA.
⁶ Section of Genomic Medicine, National Heart and Lung Institute, London, UK.
⁷ Cologne Center for Genomics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁸ School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
⁹ Departments of Medicine and Epidemiology, Columbia University, New York, NY, USA.
¹⁰ Division of Genetic Epidemiology, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
¹² Department of the Diagnostic Genomics Laboratory, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.
¹³ Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
¹⁵ Center for Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹⁶ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrjie Universiteit, Amsterdam, The Netherlands.
¹⁷ University of Leicester, Institute for Lung Health, Glenfield Hospital, Leicester, UK.
¹⁸ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁹ Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
²⁰ Department of Respiratory Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
²¹ Department of Bioengineering & Therapeutic Sciences and Medicine, University of California, San Francisco, San Francisco, CA, USA.
²² Division of Pulmonary, Allergy and Critical Care, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
²³ National Heart and Lung Institute, Imperial College London, London, UK.
²⁴ Royal Brompton Harefield National Health Service (NHS) Foundation Trust, London, UK.
²⁵ Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
²⁶ Biomedical Research Unit, Royal Brompton & Harefield National Health Service (NHS) Trust, London, UK.
²⁷ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁸ Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
²⁹ Department of Paediatrics, Imperial College London, London, UK.
³⁰ Centre for Heart and Lung Innovation, University of British Columbia, Vancouver, BC, Canada.
³¹ Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
³² Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.
³³ Department of Pediatrics, Division of Respiratory Medicine, and Department of Pediatrics, Division of Neonatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
³⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
³⁵ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³⁶ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
³⁸ Institute of Biochemistry and Genetics, Ufa Scientific Center of the Russian Academy of Sciences, Ufa, Russian Federation.
³⁹ Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
⁴⁰ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴¹ Population Genetics Laboratory, Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russian Federation.
⁴² Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA, USA.
⁴³ Broad Institute, Cambridge, MA, USA.
⁴⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴⁵ Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
⁴⁶ Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
⁴⁷ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵⁰ Asthma and Airway Disease Research Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA.
⁵¹ deCODE genetics, Amgen Inc., Reykjavik, Iceland.
⁵² School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁵³ Skin and Allergy Hospital, University of Helsinki, Helsinki, Finland.
⁵⁴ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁵ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital in Munich, Munich, Germany.
⁵⁶ Institute of Epidemiology I, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
⁵⁷ National Institute for Health and Welfare (THL), Helsinki, Finland.
⁵⁸ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA.
⁵⁹ Health Center, Department of Internal Medicine, Keio University, Tokyo, Japan.
⁶⁰ Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
⁶¹ Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.
⁶² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶³ Cell Biology Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia.
⁶⁴ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁶⁵ AbbVie Inc., Redwood City, CA, USA.
⁶⁶ Busselton Population Medical Research Institute, Perth, Western Australia, Australia.
⁶⁷ School of Population and Global Health, University of Western Australia, Nedlands, Western Australia, Australia.
⁶⁸ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
⁶⁹ University of Basel, Basel, Switzerland.
⁷⁰ Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.
⁷¹ The Generation R Study Group, Department of Pediatrics and Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷² Department of Pulmonary Physiology and Sleep Medicine, Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁷³ School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
⁷⁴ Department of Medical Sciences: Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden.
⁷⁵ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
⁷⁶ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁷⁷ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁷⁸ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁷⁹ MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
⁸⁰ School of Science and Health, Western Sydney University, Sydney, New South Wales, Australia.
⁸¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸² Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
⁸³ Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
⁸⁴ Department of Anesthesiology, Perioperative and Pain Medicine, Division of Critical Care Medicine, Boston Children's Hospital, Boston, MA, USA.
⁸⁵ Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.
⁸⁶ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russian Federation.
⁸⁷ University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands.
⁸⁸ Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.
⁸⁹ Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
⁹⁰ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹¹ Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁹² Divison of Allergy and Clinical Immunology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁹³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁹⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁹⁵ Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
⁹⁶ Department of Pulmonary Medicine, University of Turku and Turku University Hospital, Turku, Finland.
⁹⁷ Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada.
⁹⁸ Centre de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada.
⁹⁹ McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada.
¹⁰⁰ Pediatric Pneumology and Immunology, Charité Universitätsmedizin, Berlin, Germany.
¹⁰¹ Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany.
¹⁰² Pediatric Allergology, Experimental and Clinical Research Center, Charité Universitätsmedizin, Berlin, Germany.
¹⁰³ Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
¹⁰⁴ Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
¹⁰⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰⁶ Division of General Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰⁷ National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
¹⁰⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰⁹ Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
¹¹⁰ Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹¹ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
¹¹² Bristol Bioresource Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹¹³ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹¹⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹¹⁵ Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
¹¹⁶ Sachs Children's Hospital, Stockholm, Sweden.
¹¹⁷ Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹¹⁸ Schools of Population Health and of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
¹¹⁹ Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA.
¹²⁰ University Medical Center Groningen, Department of Pulmonology, University of Groningen, Groningen, The Netherlands.
¹²¹ Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹²² Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹²³ The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
¹²⁴ Department of Faculty Pediatrics, Siberian State Medical University, Tomsk, Russian Federation.
¹²⁵ Analytic and Translational Genetics Unit, Departments of Medicine, of Neurology and of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹²⁶ The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
¹²⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹²⁸ Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.
¹²⁹ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹³⁰ Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
¹³¹ Hubert Department of Global Health, Mory University, Atlanta, GA, USA.
¹³² Center for Population Health Research, National Institute of Public Health, Cuernavaca, Mexico.
¹³³ Department of Psychiatry, Kern Medical, Bakersfield, CA, USA.
¹³⁴ Department of Public Health, Section for Environment, Occupation & Health, Aarhus University, Aarhus, Denmark.
¹³⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
¹³⁶ Department of Faculty Therapy, Siberian State Medical University, Tomsk, Russian Federation.
¹³⁷ University Hospital of South Manchester, National Health Service (NHS) Foundation Trust, Manchester, UK.
¹³⁸ Institut National de la Santé et de la Recherche Médicale (INSERM) U1209, Institute for Advanced Biosciences, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France.
¹³⁹ Université de Grenoble Alpes/CNRS UMR5309, Institute for Advanced Biosciences, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France.
¹⁴⁰ Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁴¹ Population Health Research Institute, St George's University of London, London, UK.
¹⁴² Netherlands Healthcare Inspectorate, The Hague, The Netherlands.
¹⁴³ Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁴⁴ Institute for Respiratory Health and Harry Perkins Institute of Medical Research, University of Western Australia and The Lung Health Clinic, Nedlands, Western Australia, Australia.
¹⁴⁵ Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹⁴⁶ Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁴⁷ The Generation R Study Group, Department of Pediatrics, Division of Respiratory Medicine and Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁴⁸ Department of Pediatrics, Marien-Hospital Wesel, Wesel, Germany.
¹⁴⁹ Dr. Von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
¹⁵⁰ German Center for Lung Research, Munich, Germany.
¹⁵¹ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
¹⁵² Undergraduate Training and Education Center (UTEC), Jackson Heart Study, Tougaloo College, Jackson, MI, USA.
¹⁵³ Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden.
¹⁵⁴ Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA.
¹⁵⁵ Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
¹⁵⁶ School of Nursing, University of Michigan, Ann Arbor, MI, USA.
¹⁵⁷ Department of Human Genetics, University of Chicago, Chicago, IL, USA.
¹⁵⁸ Departments of Statistics, Human Genetics and Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA. nicolae@galton.uchicago.edu.

^# Contributed equally.

PMID: 29273806
PMCID: PMC5901974
DOI: 10.1038/s41588-017-0014-7

Meta-Analysis

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Florence Demenais et al. Nat Genet. 2018 Jan.

. 2018 Jan;50(1):42-53.

doi: 10.1038/s41588-017-0014-7. Epub 2017 Dec 22.

Authors

Affiliations

¹ Genetic Variation and Human Diseases Unit (UMR-946), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. florence.demenais@inserm.fr.
² Institut Universitaire d'Hématologie, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France. florence.demenais@inserm.fr.
³ Genetic Variation and Human Diseases Unit (UMR-946), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
⁴ Institut Universitaire d'Hématologie, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France.
⁵ Division of Biomedical Informatics and Personalized Medicine, Colorado Center for Personalized Medicine, University of Colorado, Denver, CO, USA.
⁶ Section of Genomic Medicine, National Heart and Lung Institute, London, UK.
⁷ Cologne Center for Genomics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁸ School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
⁹ Departments of Medicine and Epidemiology, Columbia University, New York, NY, USA.
¹⁰ Division of Genetic Epidemiology, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
¹² Department of the Diagnostic Genomics Laboratory, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.
¹³ Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
¹⁵ Center for Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
¹⁶ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrjie Universiteit, Amsterdam, The Netherlands.
¹⁷ University of Leicester, Institute for Lung Health, Glenfield Hospital, Leicester, UK.
¹⁸ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁹ Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
²⁰ Department of Respiratory Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
²¹ Department of Bioengineering & Therapeutic Sciences and Medicine, University of California, San Francisco, San Francisco, CA, USA.
²² Division of Pulmonary, Allergy and Critical Care, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
²³ National Heart and Lung Institute, Imperial College London, London, UK.
²⁴ Royal Brompton Harefield National Health Service (NHS) Foundation Trust, London, UK.
²⁵ Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
²⁶ Biomedical Research Unit, Royal Brompton & Harefield National Health Service (NHS) Trust, London, UK.
²⁷ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁸ Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
²⁹ Department of Paediatrics, Imperial College London, London, UK.
³⁰ Centre for Heart and Lung Innovation, University of British Columbia, Vancouver, BC, Canada.
³¹ Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
³² Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.
³³ Department of Pediatrics, Division of Respiratory Medicine, and Department of Pediatrics, Division of Neonatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
³⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
³⁵ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³⁶ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
³⁸ Institute of Biochemistry and Genetics, Ufa Scientific Center of the Russian Academy of Sciences, Ufa, Russian Federation.
³⁹ Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
⁴⁰ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴¹ Population Genetics Laboratory, Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russian Federation.
⁴² Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA, USA.
⁴³ Broad Institute, Cambridge, MA, USA.
⁴⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴⁵ Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
⁴⁶ Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
⁴⁷ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵⁰ Asthma and Airway Disease Research Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA.
⁵¹ deCODE genetics, Amgen Inc., Reykjavik, Iceland.
⁵² School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁵³ Skin and Allergy Hospital, University of Helsinki, Helsinki, Finland.
⁵⁴ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁵ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital in Munich, Munich, Germany.
⁵⁶ Institute of Epidemiology I, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
⁵⁷ National Institute for Health and Welfare (THL), Helsinki, Finland.
⁵⁸ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA.
⁵⁹ Health Center, Department of Internal Medicine, Keio University, Tokyo, Japan.
⁶⁰ Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
⁶¹ Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.
⁶² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶³ Cell Biology Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia.
⁶⁴ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁶⁵ AbbVie Inc., Redwood City, CA, USA.
⁶⁶ Busselton Population Medical Research Institute, Perth, Western Australia, Australia.
⁶⁷ School of Population and Global Health, University of Western Australia, Nedlands, Western Australia, Australia.
⁶⁸ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
⁶⁹ University of Basel, Basel, Switzerland.
⁷⁰ Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.
⁷¹ The Generation R Study Group, Department of Pediatrics and Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷² Department of Pulmonary Physiology and Sleep Medicine, Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁷³ School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
⁷⁴ Department of Medical Sciences: Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden.
⁷⁵ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
⁷⁶ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁷⁷ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁷⁸ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁷⁹ MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
⁸⁰ School of Science and Health, Western Sydney University, Sydney, New South Wales, Australia.
⁸¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸² Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
⁸³ Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
⁸⁴ Department of Anesthesiology, Perioperative and Pain Medicine, Division of Critical Care Medicine, Boston Children's Hospital, Boston, MA, USA.
⁸⁵ Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.
⁸⁶ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russian Federation.
⁸⁷ University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands.
⁸⁸ Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.
⁸⁹ Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
⁹⁰ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹¹ Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁹² Divison of Allergy and Clinical Immunology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁹³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁹⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁹⁵ Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
⁹⁶ Department of Pulmonary Medicine, University of Turku and Turku University Hospital, Turku, Finland.
⁹⁷ Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada.
⁹⁸ Centre de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada.
⁹⁹ McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada.
¹⁰⁰ Pediatric Pneumology and Immunology, Charité Universitätsmedizin, Berlin, Germany.
¹⁰¹ Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany.
¹⁰² Pediatric Allergology, Experimental and Clinical Research Center, Charité Universitätsmedizin, Berlin, Germany.
¹⁰³ Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
¹⁰⁴ Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
¹⁰⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰⁶ Division of General Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰⁷ National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
¹⁰⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰⁹ Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
¹¹⁰ Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹¹ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
¹¹² Bristol Bioresource Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹¹³ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹¹⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹¹⁵ Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
¹¹⁶ Sachs Children's Hospital, Stockholm, Sweden.
¹¹⁷ Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹¹⁸ Schools of Population Health and of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
¹¹⁹ Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA.
¹²⁰ University Medical Center Groningen, Department of Pulmonology, University of Groningen, Groningen, The Netherlands.
¹²¹ Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹²² Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹²³ The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
¹²⁴ Department of Faculty Pediatrics, Siberian State Medical University, Tomsk, Russian Federation.
¹²⁵ Analytic and Translational Genetics Unit, Departments of Medicine, of Neurology and of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹²⁶ The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
¹²⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹²⁸ Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.
¹²⁹ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹³⁰ Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
¹³¹ Hubert Department of Global Health, Mory University, Atlanta, GA, USA.
¹³² Center for Population Health Research, National Institute of Public Health, Cuernavaca, Mexico.
¹³³ Department of Psychiatry, Kern Medical, Bakersfield, CA, USA.
¹³⁴ Department of Public Health, Section for Environment, Occupation & Health, Aarhus University, Aarhus, Denmark.
¹³⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
¹³⁶ Department of Faculty Therapy, Siberian State Medical University, Tomsk, Russian Federation.
¹³⁷ University Hospital of South Manchester, National Health Service (NHS) Foundation Trust, Manchester, UK.
¹³⁸ Institut National de la Santé et de la Recherche Médicale (INSERM) U1209, Institute for Advanced Biosciences, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France.
¹³⁹ Université de Grenoble Alpes/CNRS UMR5309, Institute for Advanced Biosciences, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France.
¹⁴⁰ Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁴¹ Population Health Research Institute, St George's University of London, London, UK.
¹⁴² Netherlands Healthcare Inspectorate, The Hague, The Netherlands.
¹⁴³ Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁴⁴ Institute for Respiratory Health and Harry Perkins Institute of Medical Research, University of Western Australia and The Lung Health Clinic, Nedlands, Western Australia, Australia.
¹⁴⁵ Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹⁴⁶ Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁴⁷ The Generation R Study Group, Department of Pediatrics, Division of Respiratory Medicine and Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁴⁸ Department of Pediatrics, Marien-Hospital Wesel, Wesel, Germany.
¹⁴⁹ Dr. Von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
¹⁵⁰ German Center for Lung Research, Munich, Germany.
¹⁵¹ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
¹⁵² Undergraduate Training and Education Center (UTEC), Jackson Heart Study, Tougaloo College, Jackson, MI, USA.
¹⁵³ Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden.
¹⁵⁴ Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA.
¹⁵⁵ Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
¹⁵⁶ School of Nursing, University of Michigan, Ann Arbor, MI, USA.
¹⁵⁷ Department of Human Genetics, University of Chicago, Chicago, IL, USA.
¹⁵⁸ Departments of Statistics, Human Genetics and Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA. nicolae@galton.uchicago.edu.

^# Contributed equally.

PMID: 29273806
PMCID: PMC5901974
DOI: 10.1038/s41588-017-0014-7

Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors who are affiliated with deCODE (D.F.G., I.J., K.S., U.T., G.T.) are employees of deCODE genetics/AMGEN. All other co-authors did not declare any conflict of interest

Figures

**Figure 1**
Manhattan plots of the results of European-ancestry and multi-ancestry random-effects meta-analyses of asthma risk. (a) The European-ancestry meta-analysis pertains to 19,954 cases and 107,715 controls. (b) The multi-ancestry meta-analysis pertains to 23,948 cases and 118,538 controls. Each locus is annotated by its cytogenetic band location. The × axis represents chromosomal location and the y axis represents −log₁₀ (P value) for tests of association between SNPs and asthma. Black, previously known loci; red, new loci identified in the European-ancestry meta-analysis; blue, additional new loci identified in the multi-ancestry meta-analysis The dashed horizontal line denotes P=5×10⁻⁸.

**Figure 2**
GRAIL circle plot of connectivity between genes at asthma risk loci. The 17 asthma risk loci are along the outer ring (the 10p14 locus was ignored because it corresponds to a gene desert); the internal ring represents the genes at these loci. The width of the lines drawn between genes corresponds to the strength of the literature-based connectivity, with thicker lines representing stronger connections.

See this image and copyright information in PMC

References

1. Akinbami LJ, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001–2010. NCHS Data Brief. 2012:1–8. - PubMed
1. Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD. Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis. 1990;142:1351–8. - PubMed
1. Welter D, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42:D1001–6. - PMC - PubMed
1. Igartua C, et al. Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nat Commun. 2015;6:5965. - PMC - PubMed
1. Bouzigon E, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008;359:1985–94. - PubMed

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Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

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Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

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Conflict of interest statement

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