Risk loci for chronic obstructive pulmonary disease: A genome-wide association study and meta-analysis

The NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators

Research output: Contribution to journalArticle

Abstract

Background: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. Methods: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10-7in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p-8). Findings: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10-14), FAM13A (p=1·12 × 10-14), and HHIP (p=1·57 × 10-12). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10-9). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10-9). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p-9) and TGFB2 (overall joint meta-analysis p=8·3 × 10-9). Interpretation: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. Funding: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

Original languageEnglish (US)
Pages (from-to)214-225
Number of pages12
JournalThe Lancet Respiratory Medicine
Volume2
Issue number3
DOIs
StatePublished - 2014

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Genome-Wide Association Study
Chronic Obstructive Pulmonary Disease
Meta-Analysis
Joints
National Heart, Lung, and Blood Institute (U.S.)
Centers for Medicare and Medicaid Services (U.S.)
United States Department of Veterans Affairs
Health Services Research
Norway
African Americans
Single Nucleotide Polymorphism
Cohort Studies
Genome

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Risk loci for chronic obstructive pulmonary disease : A genome-wide association study and meta-analysis. / The NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators.

In: The Lancet Respiratory Medicine, Vol. 2, No. 3, 2014, p. 214-225.

Research output: Contribution to journalArticle

The NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators. / Risk loci for chronic obstructive pulmonary disease : A genome-wide association study and meta-analysis. In: The Lancet Respiratory Medicine. 2014 ; Vol. 2, No. 3. pp. 214-225.
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AU - The NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators

AU - Cho, Michael H.

AU - McDonald, Merry Lynn N

AU - Zhou, Xiaobo

AU - Mattheisen, Manuel

AU - Castaldi, Peter J.

AU - Hersh, Craig P.

AU - DeMeo, Dawn L.

AU - Sylvia, Jody S.

AU - Ziniti, John

AU - Laird, Nan M.

AU - Lange, Christoph

AU - Litonjua, Augusto A.

AU - Sparrow, David

AU - Casaburi, Richard

AU - Barr, R. Graham

AU - Regan, Elizabeth A.

AU - Make, Barry J.

AU - Hokanson, John E.

AU - Lutz, Sharon

AU - Dudenkov, Tanda Murray

AU - Farzadegan, Homayoon

AU - Hetmanski, Jacqueline B.

AU - Tal-Singer, Ruth

AU - Lomas, David A.

AU - Bakke, Per

AU - Gulsvik, Amund

AU - Crapo, James D.

AU - Silverman, Edwin K.

AU - Beaty, Terri L

PY - 2014

Y1 - 2014

N2 - Background: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. Methods: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10-7in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p-8). Findings: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10-14), FAM13A (p=1·12 × 10-14), and HHIP (p=1·57 × 10-12). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10-9). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10-9). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p-9) and TGFB2 (overall joint meta-analysis p=8·3 × 10-9). Interpretation: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. Funding: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

AB - Background: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. Methods: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10-7in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p-8). Findings: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10-14), FAM13A (p=1·12 × 10-14), and HHIP (p=1·57 × 10-12). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10-9). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10-9). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p-9) and TGFB2 (overall joint meta-analysis p=8·3 × 10-9). Interpretation: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. Funding: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

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