Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene

Craig P. Hersh, Sreekumar G. Pillai, Guohua Zhu, David A. Lomas, Per Bakke, Amund Gulsvik, Dawn L. DeMeo, Barbara J. Klanderman, Ross Lazarus, Augusto A. Litonjua, David Sparrow, John J. Reilly, Alvar Agusti, Peter M.A. Calverley, Claudio F. Donner, Robert D. Levy, Barry J. Make, Peter D. Paré, Stephen I. Rennard, Jørgen VestboEmiel F.M. Wouters, Mary Beth Scholand, Hilary Coon, John Hoidal, Edwin K. Silverman

Research output: Contribution to journalArticle

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Abstract

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q. Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q. Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study. Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10-5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5. Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.

Original languageEnglish (US)
Pages (from-to)605-613
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume182
Issue number5
DOIs
StatePublished - Sep 1 2010

Fingerprint

Chromosome Mapping
Disease Susceptibility
Chronic Obstructive Pulmonary Disease
Single Nucleotide Polymorphism
Genes
Chromosomes
Nucleotide Mapping
DNA Helicases
Genetic Linkage
Emphysema
Genetic Association Studies
Norway
Case-Control Studies
Genotype
Lung

Keywords

  • Emphysema
  • Genetic linkage
  • Metaanalysis
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene. / Hersh, Craig P.; Pillai, Sreekumar G.; Zhu, Guohua; Lomas, David A.; Bakke, Per; Gulsvik, Amund; DeMeo, Dawn L.; Klanderman, Barbara J.; Lazarus, Ross; Litonjua, Augusto A.; Sparrow, David; Reilly, John J.; Agusti, Alvar; Calverley, Peter M.A.; Donner, Claudio F.; Levy, Robert D.; Make, Barry J.; Paré, Peter D.; Rennard, Stephen I.; Vestbo, Jørgen; Wouters, Emiel F.M.; Scholand, Mary Beth; Coon, Hilary; Hoidal, John; Silverman, Edwin K.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 182, No. 5, 01.09.2010, p. 605-613.

Research output: Contribution to journalArticle

Hersh, CP, Pillai, SG, Zhu, G, Lomas, DA, Bakke, P, Gulsvik, A, DeMeo, DL, Klanderman, BJ, Lazarus, R, Litonjua, AA, Sparrow, D, Reilly, JJ, Agusti, A, Calverley, PMA, Donner, CF, Levy, RD, Make, BJ, Paré, PD, Rennard, SI, Vestbo, J, Wouters, EFM, Scholand, MB, Coon, H, Hoidal, J & Silverman, EK 2010, 'Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene', American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 5, pp. 605-613. https://doi.org/10.1164/rccm.200910-1586OC
Hersh, Craig P. ; Pillai, Sreekumar G. ; Zhu, Guohua ; Lomas, David A. ; Bakke, Per ; Gulsvik, Amund ; DeMeo, Dawn L. ; Klanderman, Barbara J. ; Lazarus, Ross ; Litonjua, Augusto A. ; Sparrow, David ; Reilly, John J. ; Agusti, Alvar ; Calverley, Peter M.A. ; Donner, Claudio F. ; Levy, Robert D. ; Make, Barry J. ; Paré, Peter D. ; Rennard, Stephen I. ; Vestbo, Jørgen ; Wouters, Emiel F.M. ; Scholand, Mary Beth ; Coon, Hilary ; Hoidal, John ; Silverman, Edwin K. / Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene. In: American Journal of Respiratory and Critical Care Medicine. 2010 ; Vol. 182, No. 5. pp. 605-613.
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T1 - Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene

AU - Hersh, Craig P.

AU - Pillai, Sreekumar G.

AU - Zhu, Guohua

AU - Lomas, David A.

AU - Bakke, Per

AU - Gulsvik, Amund

AU - DeMeo, Dawn L.

AU - Klanderman, Barbara J.

AU - Lazarus, Ross

AU - Litonjua, Augusto A.

AU - Sparrow, David

AU - Reilly, John J.

AU - Agusti, Alvar

AU - Calverley, Peter M.A.

AU - Donner, Claudio F.

AU - Levy, Robert D.

AU - Make, Barry J.

AU - Paré, Peter D.

AU - Rennard, Stephen I.

AU - Vestbo, Jørgen

AU - Wouters, Emiel F.M.

AU - Scholand, Mary Beth

AU - Coon, Hilary

AU - Hoidal, John

AU - Silverman, Edwin K.

PY - 2010/9/1

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N2 - Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q. Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q. Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study. Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10-5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5. Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.

AB - Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q. Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q. Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study. Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10-5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5. Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.

KW - Emphysema

KW - Genetic linkage

KW - Metaanalysis

KW - Single nucleotide polymorphism

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