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

Sharon M Lutz, Michael H Cho, Kendra Young, Craig P Hersh, Peter J Castaldi, Merry-Lynn McDonald, Elizabeth Regan, Manuel Mattheisen, Dawn L DeMeo, Margaret Parker, Marilyn Foreman, Barry J Make, Robert L Jensen, Richard Casaburi, David A Lomas, Surya P Bhatt, Per Bakke, Amund Gulsvik, James D Crapo, Terri H Beaty, Nan M Laird, Christoph Lange, John E Hokanson, Edwin K Silverman, ECLIPSE Investigators, COPDGene Investigators, 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, Sharon M Lutz, Michael H Cho, Kendra Young, Craig P Hersh, Peter J Castaldi, Merry-Lynn McDonald, Elizabeth Regan, Manuel Mattheisen, Dawn L DeMeo, Margaret Parker, Marilyn Foreman, Barry J Make, Robert L Jensen, Richard Casaburi, David A Lomas, Surya P Bhatt, Per Bakke, Amund Gulsvik, James D Crapo, Terri H Beaty, Nan M Laird, Christoph Lange, John E Hokanson, Edwin K Silverman, ECLIPSE Investigators, COPDGene Investigators, 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

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.

Figures

Fig. 1
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
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

References

    1. Minino A, Xu J, Kochanek K. Deaths: preliminary data for 2008. Natl Vital Stat Rep. 2010;59:1–52.
    1. Wan ES, Silverman EK. Genetics of COPD and emphysema. Chest. 2009;136:859–66. doi: 10.1378/chest.09-0555.
    1. Weiss ST. Lung function and airway diseases. Nat Genet. 2010;42(1):14–6. doi: 10.1038/ng0110-14.
    1. Silverman EK, Vestbo J, Agusti A, Anderson W, Bakke PS, Barnes KC, et al. Opportunities and challenges in the genetics of COPD 2010: an International COPD Genetics Conference report. COPD. 2011;8:121–35. doi: 10.3109/15412555.2011.558864.
    1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: Gold executive summary. Am J Respir Crit Care Med. 2007;176:532–55. doi: 10.1164/rccm.200703-456SO.
    1. Wilk JB, DeStefano AL, Arnett DK, Rich SS, Djousse L, Crapo RO, et al. A genome-wide scan of pulmonary function measures in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Respir Crit Care Med. 2003;167:1528–33. doi: 10.1164/rccm.200207-755OC.
    1. Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 2009;3(5) doi: 10.1371/journal.pgen.1000429.
    1. Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet. 2010;42:45–52. doi: 10.1038/ng.500.
    1. Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet. 2010;42:36–44. doi: 10.1038/ng.501.
    1. Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet. 2011;43:1082–90. doi: 10.1038/ng.941.
    1. Wilk JB, Shrine NRG, Loehr LR, Zhao JH, Manichaikul A, Lopez LM, et al. Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction. Am J Respir Crit Care Med. 2012;186(7):622–32. doi: 10.1164/rccm.201202-0366OC.
    1. Siedlinski M, Cho MH, Bakke P, Gulsvik A, Lomas DA, Anderson W, et al. Genome-wide association study of smoking behaviours in patients with COPD. Thorax. 2011;66(10):894–902. doi: 10.1136/thoraxjnl-2011-200154.
    1. Thyagarajan B, Wojczynski M, Minster RL, Sanders J, Barral S, Christiansen L, et al. Genetic variants associated with lung function: the long life study. Respir Res. 2014;15:134. doi: 10.1186/s12931-014-0134-x.
    1. Lambrechts D, Buysschaert I, Zanen P, Coolen J, Lays N, Cuppens H, et al. The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema. Am J Respir Crit Care Med. 2010;181:486–93. doi: 10.1164/rccm.200909-1364OC.
    1. Castaldi PJ, Cho MH, Litonjua AA, Bakke P, Gulsvik A, Lomas DA, et al. The association of genome-wide significant spirometric loci with COPD susceptibility. Am J Respir Cell Mol Biol. 2011;45:1147–53. doi: 10.1165/rcmb.2011-0055OC.
    1. DeMeo DL, Mariani T, Bhattacharya S, Srisuma S, Lange C, Litonjua A, et al. Integration of genomic and genetic approached implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet. 2009;85:493–502. doi: 10.1016/j.ajhg.2009.09.004.
    1. Zhang J, Summah H, Zhu YG, Qu JM. Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis. Respir Res. 2011;12:158. doi: 10.1186/1465-9921-12-158.
    1. Hardin M, Zielinski J, Wan ES, Hersh CP, Castaldi PJ, Schwinder E, et al. CHRNA3/5, IREB2, and ADCY2 Are Associated with Severe Chronic Obstructive Pulmonary Disease in Poland. Am J Respir Cell Mol Biol. 2012;47(2):203–8. doi: 10.1165/rcmb.2012-0011OC.
    1. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008;452:633–7. doi: 10.1038/nature06885.
    1. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40:616–22. doi: 10.1038/ng.109.
    1. Gu M, Dong X, Zhang X, Wang X, Qi Y, Yu J, et al. Strong Association between Two Polymorphisms 15q25.1 on and Lung Cancer Risk: A Meta-Analysis. Plos ONE. 2012;7(6) doi: 10.1371/journal.pone.0037970.
    1. Spitz MR, Amos CI, Dong Q, Lin J, Wu X. The CHRNA5-A3 Region on Chr 15q24-25.1 Is a Risk Factor Both for Nicotine Dependence and for Lung Cancer. J Natl Cancer Inst. 2008;100:1552–6. doi: 10.1093/jnci/djn363.
    1. Sakoda LC, Loomis MM, Doherty JA, Neuhouser ML, Barnett MJ, Thornquist MD, et al. Chr 15q24-25.1 variants, diet, and lung cancer susceptibility in cigarette smokers. Cancer Causes Control. 2011;22:449–61. doi: 10.1007/s10552-010-9716-1.
    1. Siedlinski M, Tingley D, Lipman PJ, Cho MH, Litonjua AA, Sparrow D, et al. Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility. Hum Genet. 2013;132(4):431–41. doi: 10.1007/s00439-012-1262-3.
    1. Cho MH, McDonald MN, Zhou X, Siedlinski M, Hersh CP, Demeo DL, et al. A genome-wide association identifies risk loci for severe chronic obstructive pulmonary disease. Lancet Respir. 2014;2:214–25. doi: 10.1016/S2213-2600(14)70002-5.
    1. Zhou X, Baron RM, Hardin M, Cho MH, Zielinski J, Hawrylkiewicz I, et al. Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Hum Mol Genet. 2012;21:1325–35. doi: 10.1093/hmg/ddr569.
    1. Young RP, Whittington CF, Hopkins RJ, Hay BA, Epton MJ, Black PN, et al. Chr 4q31 locus in COPD is also associated with lung cancer. Eur Respir J. 2010;36:1375–82. doi: 10.1183/09031936.00033310.
    1. Van Durme YM, Eijgelsheim M, Joos GF, Hofman A, Uitterlinden AG, Brusselle GG, et al. Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study. Eur Respir J. 2010;36:89–95. doi: 10.1183/09031936.00129509.
    1. Young RP, Hopkins RJ, Hay BA, Whittington CF, Epton MJ, Gamble GD. FAM13A locus in COPD is independently associated with lung cancer–evidence of a molecular genetic link between COPD and lung cancer. Appl Clin Genet. 2011;4:1–10.
    1. Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, et al. Genome-wide study of percent emphysema on computed tomography in the general population. The multi-ethnic study of atherosclerosis lung/SNP Health Association Resource Study. Am J Respir Crit Care Med. 2014;189(4):408–18. doi: 10.1164/rccm.201306-1061OC.
    1. Kajiho H, Saito K, Tsujita K, Kontani K, Araki Y, Kurosu H, et al. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J Cell Sci. 2003;116:4159–68. doi: 10.1242/jcs.00718.
    1. Saito K, Murai J, Kajiho H, Kontani K, Kurosu H, Katada T. A novel binding protein composed of homophilic tetramer exhibits unique properties for the small GTPase Rab5. J Biol Chem. 2002;277:3412–8. doi: 10.1074/jbc.M106276200.
    1. Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, et al. A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet. 2001;68:515–22. doi: 10.1086/318198.
    1. Wang L, Zang W, Liu J, Xie D, Ji W, Pan Y, et al. Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis. PLoS One. 2013;8(4) doi: 10.1371/journal.pone.0059556.
    1. Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, Demeo DL, et al. A genome-wide association study of COPD identifies a susceptibility locus on chr 19q13. Hum Mol Genet. 2012;21:947–57. doi: 10.1093/hmg/ddr524.
    1. Lutz SM, Hokanson JE, Lange C. An alternative hypothesis testing strategy for secondary phenotype data in case–control genetic association studies. Front Genet. 2014; (In Press) (doi:10.3389/fgene.2014.00188)
    1. Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, et al. Genetic epidemiology of COPD (COPDGene) study design. COPD. 2010;7:32–43. doi: 10.3109/15412550903499522.
    1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–38. doi: 10.1183/09031936.05.00034805.
    1. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012;44:955–9. doi: 10.1038/ng.2354.
    1. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR. MaCH: sing sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010;834:816–34. doi: 10.1002/gepi.20533.
    1. 1000 Genomes Project Consortium. Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2010;491:56–65.
    1. Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) Eur Respir J. 2008;31:869–73. doi: 10.1183/09031936.00111707.
    1. Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): Identification of two major susceptibility loci. PLoS Genet. 2009;5(3) doi: 10.1371/journal.pgen.1000421.
    1. Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP, Hersh CP, et al. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat Genet. 2010;42(3):200–1. doi: 10.1038/ng.535.
    1. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. doi: 10.1086/519795.
    1. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1. doi: 10.1093/bioinformatics/btq340.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe