Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects

National Emphysema Treatment Trial Genetics, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, International COPD Genetics Network, COPDGene Investigators

Research output: Contribution to journalArticle

Abstract

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 = 1.2831028) and PPP4R4/SERPINA1 (P = 1.0131028) 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, z0.6), 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.

Original languageEnglish (US)
Pages (from-to)35-46
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume57
Issue number1
DOIs
StatePublished - Jul 1 2017

Fingerprint

Pulmonary diseases
Chronic Obstructive Pulmonary Disease
Meta-Analysis
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Lung
Forced Expiratory Volume

Keywords

  • Chronic obstructive pulmonary disease
  • Genetic epidemiology
  • Genetic risk factors; alpha-1 antitrypsin
  • Genetic risk score

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

National Emphysema Treatment Trial Genetics, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, International COPD Genetics Network, COPDGene Investigators (2017). Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects. American Journal of Respiratory Cell and Molecular Biology, 57(1), 35-46. https://doi.org/10.1165/rcmb.2016-0331OC

Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects. / National Emphysema Treatment Trial Genetics, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, International COPD Genetics Network, COPDGene Investigators.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 57, No. 1, 01.07.2017, p. 35-46.

Research output: Contribution to journalArticle

National Emphysema Treatment Trial Genetics, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, International COPD Genetics Network, COPDGene Investigators 2017, 'Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects', American Journal of Respiratory Cell and Molecular Biology, vol. 57, no. 1, pp. 35-46. https://doi.org/10.1165/rcmb.2016-0331OC
National Emphysema Treatment Trial Genetics, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, International COPD Genetics Network, COPDGene Investigators. Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects. American Journal of Respiratory Cell and Molecular Biology. 2017 Jul 1;57(1):35-46. https://doi.org/10.1165/rcmb.2016-0331OC
National Emphysema Treatment Trial Genetics, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, International COPD Genetics Network, COPDGene Investigators. / Genetic association and risk scores in a chronic obstructive pulmonary disease meta-analysis of 16,707 subjects. In: American Journal of Respiratory Cell and Molecular Biology. 2017 ; Vol. 57, No. 1. pp. 35-46.
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