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Nat Genet. 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.

Demenais F1,2, Margaritte-Jeannin P3,4, Barnes KC5, Cookson WOC6, Altmüller J7, Ang W8, Barr RG9, Beaty TH10, Becker AB11, Beilby J12, Bisgaard H13, Bjornsdottir US14, Bleecker E15, Bønnelykke K13, Boomsma DI16, Bouzigon E3,4, Brightling CE17, Brossard M3,4, Brusselle GG18,19,20, Burchard E21, Burkart KM22, Bush A23,24, Chan-Yeung M25, Chung KF23,26, Couto Alves A27, Curtin JA28, Custovic A29, Daley D25,30, de Jongste JC31, Del-Rio-Navarro BE32, Donohue KM9, Duijts L33, Eng C34, Eriksson JG35, Farrall M36,37, Fedorova Y38, Feenstra B39, Ferreira MA40; Australian Asthma Genetics Consortium (AAGC) collaborators, Freidin MB41, Gajdos Z42,43, Gauderman J44, Gehring U45, Geller F39, Genuneit J46, Gharib SA47, Gilliland F44, Granell R48,49, Graves PE50, Gudbjartsson DF51,52, Haahtela T53, Heckbert SR54, Heederik D45, Heinrich J55,56, Heliövaara M57, Henderson J48,49, Himes BE58, Hirose H59, Hirschhorn JN43,60,61, Hofman A19,62, Holt P63, Hottenga J16, Hudson TJ64,65, Hui J12,66,67, Imboden M68,69, Ivanov V70, Jaddoe VWV71, James A72,73, Janson C74, Jarvelin MR75,76,77,78, Jarvis D23,79, Jones G80, Jonsdottir I51,81, Jousilahti P57, Kabesch M82, Kähönen M83, Kantor DB84,85, Karunas AS38,86, Khusnutdinova E38,86, Koppelman GH87,88, Kozyrskyj AL89, Kreiner E13, Kubo M90, Kumar R91,92, Kumar A68,69,93, Kuokkanen M57,94, Lahousse L19,95, Laitinen T96, Laprise C97,98, Lathrop M99, Lau S100, Lee YA101,102, Lehtimäki T103, Letort S3,4, Levin AM104, Li G47, Liang L62,105, Loehr LR106, London SJ107, Loth DW19, Manichaikul A108, Marenholz I101,102, Martinez FJ50, Matheson MC109, Mathias RA110, Matsumoto K111, Mbarek H16, McArdle WL112, Melbye M39,113,114, Melén E93,115,116, Meyers D15, Michel S82, Mohamdi H3,4, Musk AW117,118, Myers RA119, Nieuwenhuis MAE88,120, Noguchi E121, O'Connor GT122,123, Ogorodova LM124, Palmer CD43,60, Palotie A94,125,126, Park JE25, Pennell CE8, Pershagen G93,115, Polonikov A70, Postma DS88,120, Probst-Hensch N68,69, Puzyrev VP41, Raby BA127, Raitakari OT128, Ramasamy A27,129, Rich SS108, Robertson CF130, Romieu I131,132, Salam MT44,133, Salomaa V57, Schlünssen V134, Scott R135, Selivanova PA136, Sigsgaard T134, Simpson A28,137, Siroux V138,139, Smith LJ140, Solodilova M70, Standl M56, Stefansson K51,81, Strachan DP141, Stricker BH19,142,143, Takahashi A90, Thompson PJ144, Thorleifsson G51, Thorsteinsdottir U51,81, Tiesler CMT56,145, Torgerson DG34, Tsunoda T90,146, Uitterlinden AG143, van der Valk RJP147, Vaysse A3,4, Vedantam S42,43, von Berg A148, von Mutius E149,150, Vonk JM88,151, Waage J13, Wareham NJ135, Weiss ST127, White WB152, Wickman M93,153, Widén E94, Willemsen G16, Williams LK154,155, Wouters IM45, Yang JJ156, Zhao JH135, Moffatt MF6, Ober C157, Nicolae DL158.

Author information

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.

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.

PMID:
29273806
PMCID:
PMC5901974
DOI:
10.1038/s41588-017-0014-7
[Indexed for MEDLINE]
Free PMC Article

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