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PLoS One. 2014 Jul 1;9(7):e100776. doi: 10.1371/journal.pone.0100776. eCollection 2014.

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

Author information

1
Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America.
2
Ontario Institute for Cancer Research and Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
3
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Healthcare Inspectorate, The Hague, the Netherlands.
4
University of Leicester, Genetic Epidemiology Group, Department of Health Sciences, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
5
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America.
6
Division of Respiratory Medicine, University Hospital of Nottingham, Nottingham, United Kingdom.
7
Computational Medicine Core, Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
8
Icelandic Heart Association, Kopavogur, Iceland; University of Iceland, Reykjavik, Iceland.
9
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
10
Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
11
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
12
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
13
Department of Thoracic Surgery and Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
14
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
15
Division of General Medicine, Pulmonary, Allergy and Critical Care, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
16
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; 22 Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
17
Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
18
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh Molecular Medicine Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
19
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
20
Biostatistics Department, Boston University School of Public Health, Boston, Massachusetts, United States of America; The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
21
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
22
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
23
Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
24
Biostatistics Department, Boston University School of Public Health, Boston, Massachusetts, United States of America.
25
Department of Internal Medicine B; Pneumology, Cardiology, Intensive Care Medicine; Field of Research: Pneumology and Pneumological Epidemiology, University Medicine Greifswald, Greifswald, Germany.
26
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America; Behavioral Health Epidemiology Program, Research Triangle Institute, Research Triangle Park, North Carolina, United States of America.
27
Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany and Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany.
28
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Rotterdam, the Netherlands.
29
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK and Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
30
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
31
Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany; Institute of General Practice, University Hospital Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
32
Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
33
Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK and Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
34
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
35
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America.
36
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
37
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK and Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
38
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
39
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
40
Department of Statistics, University of Auckland, Auckland, New Zealand.
41
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
42
College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
43
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK and Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
44
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
45
Ontario Institute for Cancer Research and Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Epidemiology and Obstetrics & Gynaecology, University of Toronto, Toronto, Ontario, Canada; Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.
46
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
47
Netherlands Consortium for Healthy Aging, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
48
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America.
49
Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
50
University of New Mexico, Albuquerque, New Mexico, United States of America.
51
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
52
Division of Population Health Sciences and Education, St George's, University of London, London, United Kingdom.
53
Department for Genetics and Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
54
Institute for Community Medicine, Study of Health In Pomerania (SHIP)/Clinical Epidemiological Research, University Medicine Greifswald, Greifswald, Germany.
55
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
56
Department of Statistical Science, Cornell University, Ithaca, New York, United States of America.
57
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
58
Florida International University, Miami, Florida, United States of America.
59
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
60
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
61
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Section of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
62
Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America; Department of Health Care Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, New York, United States of America.

Abstract

BACKGROUND:

Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS:

We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS:

The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS:

In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

PMID:
24983941
PMCID:
PMC4077649
DOI:
10.1371/journal.pone.0100776
[Indexed for MEDLINE]
Free PMC Article

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