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Nat Commun. 2018 Jul 30;9(1):2976. doi: 10.1038/s41467-018-05369-0.

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

Author information

1
Epidemiology Branch National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.
2
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, 02115, USA.
3
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
4
Department of Respiratory Medicine, Ghent University Hospital, Ghent, 9000, Belgium.
5
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000, CA, The Netherlands.
6
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
7
Department of Bioanalysis, FFW, Ghent University, Ghent, 9000, Belgium.
8
Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
9
Icelandic Heart Association, Kopavogur, 201, Iceland.
10
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
11
Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
12
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
13
Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
14
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, USA.
15
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
16
The Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolic Genetics Section, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
17
Steno Diabetes Center Copenhagen, Gentofte, 2820, Denmark.
18
Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA.
19
Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, 2305, Australia.
20
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
21
Department of Epidemiologie, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, Netherlands.
22
Division of Biostatistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA.
23
Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
24
Postgraduate Program in Epidemiology, Federal University of Pelotas, 96020-220, Pelotas, Brazil.
25
Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, UK.
26
Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
27
Integrative Bioinformatics Support Group National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.
28
The University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, V6Z 1Y6, Canada.
29
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
30
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
31
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, 20892, USA.
32
Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, 48202, USA.
33
School of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
34
Department of Biology, Loyola University Chicago, Chicago, IL, 60660, USA.
35
University of California Los Angeles, Los Angeles, CA, 90095, USA.
36
Westat, Durham, NC, 27703, USA.
37
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27599, USA.
38
Department of Health and Human Services, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
39
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
40
Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98101, USA.
41
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
42
Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA.
43
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
44
Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
45
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
46
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
47
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
48
Department of Radiology, Erasmus University Medical Center, Rotterdam, 3015 GD, The Netherlands.
49
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, 9700 AB, The Netherlands.
50
Hebrew SeniorLife, Harvard University, Boston, MA, 02131, USA.
51
Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, 48202, USA.
52
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
53
Division of Pulmonary Medicine, Allergy, and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, 15224, USA.
54
Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
55
Division of Molecular Medicine, Pathology North, NSW Health Pathology, Newcastle, NSW, 2305, Australia.
56
Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, 5000, Denmark.
57
Department of Pediatrics, Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
58
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
59
Department of Pulmonology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
60
Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, G1V 4G5, Canada.
61
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
62
Merck Research Laboratories, GpGx, Merck & Co., Inc., Kenilworth, NJ, 07033, USA.
63
Department of Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA.
64
School of Pharmacy, University of California San Francisco, San Francisco, CA, 94143, USA.
65
Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
66
Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
67
Cardiovascular Health Research Unit, Department of Health Services, University of Washington, Seattle, WA, 98101, USA.
68
Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
69
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, 01702, USA.
70
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
71
Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY, 10065, USA.
72
Department of Health Science, School of Public Health, Seoul National University, Seoul, 08826, South Korea.
73
Department of Internal Medicine and Environmental Health Center, Kangwon National University, Chuncheon, 24341, South Korea.
74
University of Colorado Denver, Denver, CO, 80204, USA.
75
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
76
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
77
Section of Genetic Medicine, The University of Chicago, Chicago, IL, 60637, USA.
78
Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherlands.
79
Department of Medicine, Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, University of Washington, Seattle, WA, 98109, USA.
80
Epidemiology Branch National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, NC, 27709, USA. london2@niehs.nih.gov.

Abstract

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

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