Clinical Trial

. 2015 Dec 3:16:138.

doi: 10.1186/s12863-015-0299-4.

A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry

Sharon M Lutz¹, Michael H Cho², Kendra Young³, Craig P Hersh⁴, Peter J Castaldi⁵, Merry-Lynn McDonald⁶, Elizabeth Regan⁷, Manuel Mattheisen⁸, Dawn L DeMeo⁹, Margaret Parker¹⁰, Marilyn Foreman¹¹, Barry J Make¹², Robert L Jensen¹³, Richard Casaburi¹⁴, David A Lomas¹⁵, Surya P Bhatt¹⁶, Per Bakke¹⁷, Amund Gulsvik¹⁸, James D Crapo¹⁹, Terri H Beaty²⁰, Nan M Laird²¹, Christoph Lange²², John E Hokanson²³, Edwin K Silverman²⁴; ECLIPSE Investigators; COPDGene Investigators

Collaborators, Affiliations

Collaborators

James Crapo, Edwin Silverman, Barry Make, Elizabeth Regan, Rochelle Lantz, Lori Stepp, Sandra Melanson, Terri Beaty, Barbara Klanderman, Nan Laird, Christoph Lange, Michael Cho, Stephanie Santorico, John Hokanson, Dawn DeMeo, Nadia Hansel, Craig Hersh, Peter Castaldi, Merry-Lynn McDonald, Jing Zhou, Manuel Mattheissen, Emily Wan, Megan Hardin, Jacqueline Hetmanski, Margaret Parker, Tanda Murray, David Lynch, Joyce Schroeder, John Newell Jr, John Reilly, Harvey Coxson, Philip Judy, Eric Hoffman, George Washko, Raul San Jose Estepar, James Ross, Mustafa Al Qaisi, Jordan Zach, Alex Kluiber, Jered Sieren, Tanya Mann, Deanna Richert, Alexander McKenzie, Jaleh Akhavan, Douglas Stinson, Robert Jensen, Homayoon Farzadegan, Stacey Meyerer, Shivam Chandan, Samantha Bragan, Douglas Everett, Andre Williams, Carla Wilson, Anna Forssen, Amber Powell, Joe Piccoli, John Hokanson, Marci Sontag, Jennifer Black-Shinn, Gregory Kinney, Sharon Lutz, Jeffrey Curtis, Ella Kazerooni, Nicola Hanania, Philip Alapat, Venkata Bandi, Kalpalatha Guntupalli, Elizabeth Guy, Antara Mallampalli, Charles Trinh, Mustafa Atik, Hasan Al-Azzawi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Alexander Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dawn DeMeo, Craig Hersh, George Washko, Francine Jacobson, Hiroto Hatabu, Peter Clarke, Ritu Gill, Andetta Hunsaker, Beatrice Trotman-Dickenson, Rachna Madan, R Graham Barr, Byron Thomashow, John Austin, Belinda D'Souza, Neil MacIntyre Jr, Lacey Washington, H Page McAdams, Richard Rosiello, Timothy Bresnahan, Joseph Bradley, Sharon Kuong, Steven Meller, Suzanne Roland, Charlene McEvoy, Joseph Tashjian, Robert Wise, Nadia Hansel, Robert Brown, Gregory Diette, Karen Horton, Richard Casaburi, Janos Porszasz, Hans Fischer, Matt Budoff, Mehdi Rambod, Amir Sharafkhaneh, Charles Trinh, Hirani Kamal, Roham Darvishi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Alexander Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dennis Niewoehner, Quentin Anderson, Kathryn Rice, Audrey Caine, Marilyn Foreman, Gloria Westney, Eugene Berkowitz, Russell Bowler, David Lynch, Joyce Schroeder, Valerie Hale, John Armstrong 2nd, Debra Dyer, Jonathan Chung, Christian Cox, Gerard Criner, Victor Kim, Nathaniel Marchetti, Aditi Satti, A James Mamary, Robert Steiner, Chandra Dass, Libby Cone, William Bailey, Mark Dransfield, Michael Wells, Surya Bhatt, Hrudaya Nath, Satinder Singh, Joe Ramsdell, Paul Friedman, Alejandro Cornellas, John Newell Jr, Edwin J R van Beek, Fernando Martinez, MeiLan Han, Ella Kazerooni, Christine Wendt, Tadashi Allen, Frank Sciurba, Joel Weissfeld, Carl Fuhrman, Jessica Bon, Danielle Hooper, Antonio Anzueto, Sandra Adams, Carlos Orozco, Mario Ruiz, Amy Mumbower, Ariel Kruger, Carlos Restrepo, Michael Lane, Y Ivanov, K Kostov, J Bourbeau, M Fitzgerald, P Hernandez, K Killian, R Levy, F Maltais, D O'Donnell, J Krepelka, J Vestbo, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, P de Mallorca, Y Feschenko, V Gavrisyuk, L Yashina, N Monogarova, P Calverley, D Lomas, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, G Giessel, M Gotfried, G Greenwald, N Hanania, D Mahler, B Make, S Rennard, C Rochester, P Scanlon, D Schuller, F Sciurba, A Sharafkhaneh, T Siler, E Silverman, A Wanner, R Wise, R ZuWallack, H Coxson, C Crim, L Edwards, D Lomas, W MacNee, E Silverman, R Tal Singer, J Vestbo, J Yates, A Agusti, P Calverley, B Celli, C Crim, B Miller, W MacNee, S Rennard, R Tal-Singer, E Wouters, J Yates

Affiliations

¹ Department of Biostatistics, University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, B119 Bldg. 500, W3128, Aurora, CO, 80045, USA. sharon.lutz@ucdenver.edu.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. remhc@channing.harvard.edu.
³ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. kendra.young@ucdenver.edu.
⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. craig.hersh@channing.harvard.edu.
⁵ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. repjc@channing.harvard.edu.
⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. remrm@channing.harvard.edu.
⁷ Department of Medicine, National Jewish Health, Denver, CO, USA. regane@njhealth.org.
⁸ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mm@hum-gen.au.dk.
⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. redld@channing.harvard.edu.
¹⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. mmparker1@gmail.com.
¹¹ Morehouse School of Medicine, Atlanta, GA, USA. mforeman@msm.edu.
¹² Department of Medicine, National Jewish Health, Denver, CO, USA. makeb@njhealth.org.
¹³ Division of Pulmonary, Allergy & Critical Care Medicine, LDS Hospital, Salt Lake City, UT, USA. ldrjens1@ihc.com.
¹⁴ Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. casaburi@ucla.edu.
¹⁵ Wolfson Institute for Biomedical Research, University College London, London, UK. d.lomas@ucl.ac.uk.
¹⁶ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. spbhatt@uab.edu.
¹⁷ Department of Clinical Science, University of Bergen, Bergen, Norway. per.bakke@med.uib.no.
¹⁸ Department of Clinical Science, University of Bergen, Bergen, Norway. amund.gulsvik@med.uib.no.
¹⁹ Department of Medicine, National Jewish Health, Denver, CO, USA. crapoj@njc.org.
²⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. tbeaty@jhsph.edu.
²¹ Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. nanlaird@gmail.com.
²² Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. langech2007@gmail.com.
²³ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. John.Hokanson@ucdenver.edu.
²⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ed.silverman@channing.harvard.edu.

PMID: 26634245
PMCID: PMC4668640
DOI: 10.1186/s12863-015-0299-4

Clinical Trial

A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry

Sharon M Lutz et al. BMC Genet. 2015.

. 2015 Dec 3:16:138.

doi: 10.1186/s12863-015-0299-4.

Authors

Collaborators

James Crapo, Edwin Silverman, Barry Make, Elizabeth Regan, Rochelle Lantz, Lori Stepp, Sandra Melanson, Terri Beaty, Barbara Klanderman, Nan Laird, Christoph Lange, Michael Cho, Stephanie Santorico, John Hokanson, Dawn DeMeo, Nadia Hansel, Craig Hersh, Peter Castaldi, Merry-Lynn McDonald, Jing Zhou, Manuel Mattheissen, Emily Wan, Megan Hardin, Jacqueline Hetmanski, Margaret Parker, Tanda Murray, David Lynch, Joyce Schroeder, John Newell Jr, John Reilly, Harvey Coxson, Philip Judy, Eric Hoffman, George Washko, Raul San Jose Estepar, James Ross, Mustafa Al Qaisi, Jordan Zach, Alex Kluiber, Jered Sieren, Tanya Mann, Deanna Richert, Alexander McKenzie, Jaleh Akhavan, Douglas Stinson, Robert Jensen, Homayoon Farzadegan, Stacey Meyerer, Shivam Chandan, Samantha Bragan, Douglas Everett, Andre Williams, Carla Wilson, Anna Forssen, Amber Powell, Joe Piccoli, John Hokanson, Marci Sontag, Jennifer Black-Shinn, Gregory Kinney, Sharon Lutz, Jeffrey Curtis, Ella Kazerooni, Nicola Hanania, Philip Alapat, Venkata Bandi, Kalpalatha Guntupalli, Elizabeth Guy, Antara Mallampalli, Charles Trinh, Mustafa Atik, Hasan Al-Azzawi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Alexander Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dawn DeMeo, Craig Hersh, George Washko, Francine Jacobson, Hiroto Hatabu, Peter Clarke, Ritu Gill, Andetta Hunsaker, Beatrice Trotman-Dickenson, Rachna Madan, R Graham Barr, Byron Thomashow, John Austin, Belinda D'Souza, Neil MacIntyre Jr, Lacey Washington, H Page McAdams, Richard Rosiello, Timothy Bresnahan, Joseph Bradley, Sharon Kuong, Steven Meller, Suzanne Roland, Charlene McEvoy, Joseph Tashjian, Robert Wise, Nadia Hansel, Robert Brown, Gregory Diette, Karen Horton, Richard Casaburi, Janos Porszasz, Hans Fischer, Matt Budoff, Mehdi Rambod, Amir Sharafkhaneh, Charles Trinh, Hirani Kamal, Roham Darvishi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Alexander Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dennis Niewoehner, Quentin Anderson, Kathryn Rice, Audrey Caine, Marilyn Foreman, Gloria Westney, Eugene Berkowitz, Russell Bowler, David Lynch, Joyce Schroeder, Valerie Hale, John Armstrong 2nd, Debra Dyer, Jonathan Chung, Christian Cox, Gerard Criner, Victor Kim, Nathaniel Marchetti, Aditi Satti, A James Mamary, Robert Steiner, Chandra Dass, Libby Cone, William Bailey, Mark Dransfield, Michael Wells, Surya Bhatt, Hrudaya Nath, Satinder Singh, Joe Ramsdell, Paul Friedman, Alejandro Cornellas, John Newell Jr, Edwin J R van Beek, Fernando Martinez, MeiLan Han, Ella Kazerooni, Christine Wendt, Tadashi Allen, Frank Sciurba, Joel Weissfeld, Carl Fuhrman, Jessica Bon, Danielle Hooper, Antonio Anzueto, Sandra Adams, Carlos Orozco, Mario Ruiz, Amy Mumbower, Ariel Kruger, Carlos Restrepo, Michael Lane, Y Ivanov, K Kostov, J Bourbeau, M Fitzgerald, P Hernandez, K Killian, R Levy, F Maltais, D O'Donnell, J Krepelka, J Vestbo, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, P de Mallorca, Y Feschenko, V Gavrisyuk, L Yashina, N Monogarova, P Calverley, D Lomas, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, G Giessel, M Gotfried, G Greenwald, N Hanania, D Mahler, B Make, S Rennard, C Rochester, P Scanlon, D Schuller, F Sciurba, A Sharafkhaneh, T Siler, E Silverman, A Wanner, R Wise, R ZuWallack, H Coxson, C Crim, L Edwards, D Lomas, W MacNee, E Silverman, R Tal Singer, J Vestbo, J Yates, A Agusti, P Calverley, B Celli, C Crim, B Miller, W MacNee, S Rennard, R Tal-Singer, E Wouters, J Yates

Affiliations

¹ Department of Biostatistics, University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, B119 Bldg. 500, W3128, Aurora, CO, 80045, USA. sharon.lutz@ucdenver.edu.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. remhc@channing.harvard.edu.
³ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. kendra.young@ucdenver.edu.
⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. craig.hersh@channing.harvard.edu.
⁵ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. repjc@channing.harvard.edu.
⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. remrm@channing.harvard.edu.
⁷ Department of Medicine, National Jewish Health, Denver, CO, USA. regane@njhealth.org.
⁸ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mm@hum-gen.au.dk.
⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. redld@channing.harvard.edu.
¹⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. mmparker1@gmail.com.
¹¹ Morehouse School of Medicine, Atlanta, GA, USA. mforeman@msm.edu.
¹² Department of Medicine, National Jewish Health, Denver, CO, USA. makeb@njhealth.org.
¹³ Division of Pulmonary, Allergy & Critical Care Medicine, LDS Hospital, Salt Lake City, UT, USA. ldrjens1@ihc.com.
¹⁴ Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. casaburi@ucla.edu.
¹⁵ Wolfson Institute for Biomedical Research, University College London, London, UK. d.lomas@ucl.ac.uk.
¹⁶ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. spbhatt@uab.edu.
¹⁷ Department of Clinical Science, University of Bergen, Bergen, Norway. per.bakke@med.uib.no.
¹⁸ Department of Clinical Science, University of Bergen, Bergen, Norway. amund.gulsvik@med.uib.no.
¹⁹ Department of Medicine, National Jewish Health, Denver, CO, USA. crapoj@njc.org.
²⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. tbeaty@jhsph.edu.
²¹ Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. nanlaird@gmail.com.
²² Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. langech2007@gmail.com.
²³ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. John.Hokanson@ucdenver.edu.
²⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ed.silverman@channing.harvard.edu.

PMID: 26634245
PMCID: PMC4668640
DOI: 10.1186/s12863-015-0299-4

Abstract

Background: Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532).

Results: Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)).

Conclusions: In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.

Trial registration: ClinicalTrials.gov NCT00292552 NCT00608764.

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Figures

**Fig. 1**
Comparison of chromosome 15 region [*CHRNA3/5, IREB2*] between NHW (a and c) and AA (b and d) in COPDGene for FEV₁ (a and b), and FEV₁/FVC (c and d). Note that there is a similar but narrower and less significant signal in AA

**Fig. 2**
Comparison of chromosome 4 region [near *HHIP*] between NHW (a) and AA (b) for FEV₁/FVC. Note that unlike for chromosome 15, there is not a similar signal in AA, although this could be due to the reduced statistical power in the smaller sample size of AA

See this image and copyright information in PMC

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A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry

Collaborators

Affiliations

A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous