Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD

Nadia Hansel, Ingo Ruczinski, Nicholas Rafaels, Don D. Sin, Denise Daley, Alla Malinina, Lili Huang, Andrew Sandford, Tanda Murray, Yoonhee Kim, Candelaria Vergara, Susan R. Heckbert, Bruce M. Psaty, Guo Li, W. Mark Elliott, Farzian Aminuddin, Josée Dupuis, George T. O'Connor, Kimberly Doheny, Alan F ScottH. Marike Boezen, Dirkje S. Postma, Joanna Smolonska, Pieter Zanen, Firdaus A. Mohamed Hoesein, Harry J. De Koning, Ronald G. Crystal, Toshiko Tanaka, Luigi Ferrucci, Edwin Silverman, Emily Wan, Jorgen Vestbo, David A. Lomas, John Connett, Robert A Wise, Enid Neptune, Rasika Mathias, Peter D. Paré, Terri L Beaty, Kathleen C. Barnes

Research output: Contribution to journalArticle

Abstract

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1-A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

Original languageEnglish (US)
Pages (from-to)79-90
Number of pages12
JournalHuman Genetics
Volume132
Issue number1
DOIs
StatePublished - Jan 2013

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Chronic Obstructive Pulmonary Disease
Genome
Lung
Single Nucleotide Polymorphism
Chromosomes, Human, Pair 10
HapMap Project
Genes
Chromosomes, Human, Pair 14
Genome-Wide Association Study
Alveolar Macrophages
Epithelium
Immunohistochemistry
Genotype
Phenotype
Gene Expression
Health
Population

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. / Hansel, Nadia; Ruczinski, Ingo; Rafaels, Nicholas; Sin, Don D.; Daley, Denise; Malinina, Alla; Huang, Lili; Sandford, Andrew; Murray, Tanda; Kim, Yoonhee; Vergara, Candelaria; Heckbert, Susan R.; Psaty, Bruce M.; Li, Guo; Elliott, W. Mark; Aminuddin, Farzian; Dupuis, Josée; O'Connor, George T.; Doheny, Kimberly; Scott, Alan F; Boezen, H. Marike; Postma, Dirkje S.; Smolonska, Joanna; Zanen, Pieter; Mohamed Hoesein, Firdaus A.; De Koning, Harry J.; Crystal, Ronald G.; Tanaka, Toshiko; Ferrucci, Luigi; Silverman, Edwin; Wan, Emily; Vestbo, Jorgen; Lomas, David A.; Connett, John; Wise, Robert A; Neptune, Enid; Mathias, Rasika; Paré, Peter D.; Beaty, Terri L; Barnes, Kathleen C.

In: Human Genetics, Vol. 132, No. 1, 01.2013, p. 79-90.

Research output: Contribution to journalArticle

Hansel, N, Ruczinski, I, Rafaels, N, Sin, DD, Daley, D, Malinina, A, Huang, L, Sandford, A, Murray, T, Kim, Y, Vergara, C, Heckbert, SR, Psaty, BM, Li, G, Elliott, WM, Aminuddin, F, Dupuis, J, O'Connor, GT, Doheny, K, Scott, AF, Boezen, HM, Postma, DS, Smolonska, J, Zanen, P, Mohamed Hoesein, FA, De Koning, HJ, Crystal, RG, Tanaka, T, Ferrucci, L, Silverman, E, Wan, E, Vestbo, J, Lomas, DA, Connett, J, Wise, RA, Neptune, E, Mathias, R, Paré, PD, Beaty, TL & Barnes, KC 2013, 'Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD', Human Genetics, vol. 132, no. 1, pp. 79-90. https://doi.org/10.1007/s00439-012-1219-6
Hansel, Nadia ; Ruczinski, Ingo ; Rafaels, Nicholas ; Sin, Don D. ; Daley, Denise ; Malinina, Alla ; Huang, Lili ; Sandford, Andrew ; Murray, Tanda ; Kim, Yoonhee ; Vergara, Candelaria ; Heckbert, Susan R. ; Psaty, Bruce M. ; Li, Guo ; Elliott, W. Mark ; Aminuddin, Farzian ; Dupuis, Josée ; O'Connor, George T. ; Doheny, Kimberly ; Scott, Alan F ; Boezen, H. Marike ; Postma, Dirkje S. ; Smolonska, Joanna ; Zanen, Pieter ; Mohamed Hoesein, Firdaus A. ; De Koning, Harry J. ; Crystal, Ronald G. ; Tanaka, Toshiko ; Ferrucci, Luigi ; Silverman, Edwin ; Wan, Emily ; Vestbo, Jorgen ; Lomas, David A. ; Connett, John ; Wise, Robert A ; Neptune, Enid ; Mathias, Rasika ; Paré, Peter D. ; Beaty, Terri L ; Barnes, Kathleen C. / Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. In: Human Genetics. 2013 ; Vol. 132, No. 1. pp. 79-90.
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abstract = "Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1-A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.",
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AU - Hansel, Nadia

AU - Ruczinski, Ingo

AU - Rafaels, Nicholas

AU - Sin, Don D.

AU - Daley, Denise

AU - Malinina, Alla

AU - Huang, Lili

AU - Sandford, Andrew

AU - Murray, Tanda

AU - Kim, Yoonhee

AU - Vergara, Candelaria

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AU - Li, Guo

AU - Elliott, W. Mark

AU - Aminuddin, Farzian

AU - Dupuis, Josée

AU - O'Connor, George T.

AU - Doheny, Kimberly

AU - Scott, Alan F

AU - Boezen, H. Marike

AU - Postma, Dirkje S.

AU - Smolonska, Joanna

AU - Zanen, Pieter

AU - Mohamed Hoesein, Firdaus A.

AU - De Koning, Harry J.

AU - Crystal, Ronald G.

AU - Tanaka, Toshiko

AU - Ferrucci, Luigi

AU - Silverman, Edwin

AU - Wan, Emily

AU - Vestbo, Jorgen

AU - Lomas, David A.

AU - Connett, John

AU - Wise, Robert A

AU - Neptune, Enid

AU - Mathias, Rasika

AU - Paré, Peter D.

AU - Beaty, Terri L

AU - Barnes, Kathleen C.

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N2 - Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1-A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

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