Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.
The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10-8) and PPP4R4/SERPINA1 (P = 1.01 × 10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Robert
0000-0003-0820-7164
R
Busch
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Brian D
0000-0001-9564-0745
BD
Hobbs
2 University of Arizona, Tucson, Arizona.
Jin
J
Zhou
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Peter J
PJ
Castaldi
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Michael J
MJ
McGeachie
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Megan E
ME
Hardin
3 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
Iwona
I
Hawrylkiewicz
3 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
Pawel
P
Sliwinski
4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Jae-Joon
JJ
Yim
5 Kangwon National University, Chuncheon, Korea.
Woo Jin
WJ
Kim
6 Seoul National University College of Medicine Boramae Medical Center, Seoul, Korea.
Deog K
DK
Kim
7 Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, Spain.
Alvar
A
Agusti
8 National Jewish Health, Denver, Colorado.
Barry J
BJ
Make
8 National Jewish Health, Denver, Colorado.
James D
JD
Crapo
9 University of Liverpool, Liverpool, United Kingdom.
Peter M
PM
Calverley
10 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero, Novara, Italy.
Claudio F
CF
Donner
11 University College London, London, United Kingdom.
David A
DA
Lomas
12 University Hospital Maastricht, Maastricht, the Netherlands.
Emiel F
EF
Wouters
13 University of Manchester, Manchester, United Kingdom.
Jørgen
J
Vestbo
14 GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania.
Ruth
R
Tal-Singer
15 University of Bergen, Bergen, Norway.
Per
P
Bakke
15 University of Bergen, Bergen, Norway.
Amund
A
Gulsvik
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Augusto A
AA
Litonjua
16 Brigham and Women's Hospital and the Veterans Administration Medical Center-Jamaica Plain, Jamaica Plain, Massachusetts.
David
D
Sparrow
17 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Peter D
PD
Paré
17 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Robert D
RD
Levy
18 University of Nebraska Medical Center, Omaha, Nebraska.
Stephen I
SI
Rennard
19 Department of Epidemiology, Bloomberg School of Public Health, the Johns Hopkins University, Baltimore, Maryland; and.
Terri H
TH
Beaty
20 Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
John
J
Hokanson
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Edwin K
EK
Silverman
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Michael H
0000-0002-4907-1657
MH
Cho
D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012129:Respiratory Function Tests; D012307:Risk Factors
alpha-1 antitrypsin; chronic obstructive pulmonary disease; genetic epidemiology; genetic risk factors; genetic risk score