Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Dana B. Hancock, María Soler Artigas, Sina A. Gharib, Amanda Henry, Ani Manichaikul, Adaikalavan Ramasamy, Daan W. Loth, Medea Imboden, Beate Koch, Wendy L. McArdle, Albert V. Smith, Joanna Smolonska, Akshay Sood, Wenbo Tang, Jemma B. Wilk, Guangju Zhai, Jing Hua Zhao, Hugues Aschard, Kristin M. Burkart, Ivan CurjuricMark Eijgelsheim, Paul Elliott, Xiangjun Gu, Tamara B. Harris, Christer Janson, Georg Homuth, Pirro G. Hysi, Jason Z. Liu, Laura R. Loehr, Kurt Lohman, Ruth J.F. Loos, Alisa K. Manning, Kristin D. Marciante, Ma'en Obeidat, Dirkje S. Postma, Melinda C. Aldrich, Guy G. Brusselle, Ting hsu Chen, Gudny Eiriksdottir, Nora Franceschini, Joachim Heinrich, Jerome I. Rotter, Cisca Wijmenga, O. Dale Williams, Amy R. Bentley, Albert Hofman, Cathy C. Laurie, Thomas Lumley, Alanna C. Morrison, Bonnie R. Joubert, Fernando Rivadeneira, David J. Couper, Stephen B. Kritchevsky, Yongmei Liu, Matthias Wjst, Louise V. Wain, Judith M. Vonk, André G. Uitterlinden, Thierry Rochat, Stephen S. Rich, Bruce M. Psaty, George T. O'Connor, Kari E. North, Daniel B. Mirel, Bernd Meibohm, Lenore J. Launer, Kay Tee Khaw, Anna Liisa Hartikainen, Christopher J. Hammond, Sven Gläser, Jonathan Marchini, Peter Kraft, Nicholas J. Wareham, Henry Völzke, Bruno H.C. Stricker, Timothy D. Spector, Nicole M. Probst-Hensch, Deborah Jarvis, Marjo Riitta Jarvelin, Susan R. Heckbert, Vilmundur Gudnason, H. Marike Boezen, R. Graham Barr, Patricia A. Cassano, David P. Strachan, Myriam Fornage, Ian P. Hall, Josée Dupuis, Martin D. Tobin, Stephanie J. London

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA=5.00×10-11), HLA-DQB1 and HLA-DQA2 (smallest PJMA=4.35×10-9), and KCNJ2 and SOX9 (smallest PJMA=1.28×10-8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Original languageEnglish (US)
Article numbere1003098
JournalPLoS genetics
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2012

Fingerprint

lung function
meta-analysis
smoking
single nucleotide polymorphism
Single Nucleotide Polymorphism
Meta-Analysis
polymorphism
genome
Joints
Smoking
Genome
Lung
loci
lungs
smoking (habit)
Genetic Loci
Genome-Wide Association Study
Vital Capacity
Forced Expiratory Volume
phenotype

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Hancock, D. B., Artigas, M. S., Gharib, S. A., Henry, A., Manichaikul, A., Ramasamy, A., ... London, S. J. (2012). Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function. PLoS genetics, 8(12), [e1003098]. https://doi.org/10.1371/journal.pgen.1003098

Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function. / Hancock, Dana B.; Artigas, María Soler; Gharib, Sina A.; Henry, Amanda; Manichaikul, Ani; Ramasamy, Adaikalavan; Loth, Daan W.; Imboden, Medea; Koch, Beate; McArdle, Wendy L.; Smith, Albert V.; Smolonska, Joanna; Sood, Akshay; Tang, Wenbo; Wilk, Jemma B.; Zhai, Guangju; Zhao, Jing Hua; Aschard, Hugues; Burkart, Kristin M.; Curjuric, Ivan; Eijgelsheim, Mark; Elliott, Paul; Gu, Xiangjun; Harris, Tamara B.; Janson, Christer; Homuth, Georg; Hysi, Pirro G.; Liu, Jason Z.; Loehr, Laura R.; Lohman, Kurt; Loos, Ruth J.F.; Manning, Alisa K.; Marciante, Kristin D.; Obeidat, Ma'en; Postma, Dirkje S.; Aldrich, Melinda C.; Brusselle, Guy G.; Chen, Ting hsu; Eiriksdottir, Gudny; Franceschini, Nora; Heinrich, Joachim; Rotter, Jerome I.; Wijmenga, Cisca; Williams, O. Dale; Bentley, Amy R.; Hofman, Albert; Laurie, Cathy C.; Lumley, Thomas; Morrison, Alanna C.; Joubert, Bonnie R.; Rivadeneira, Fernando; Couper, David J.; Kritchevsky, Stephen B.; Liu, Yongmei; Wjst, Matthias; Wain, Louise V.; Vonk, Judith M.; Uitterlinden, André G.; Rochat, Thierry; Rich, Stephen S.; Psaty, Bruce M.; O'Connor, George T.; North, Kari E.; Mirel, Daniel B.; Meibohm, Bernd; Launer, Lenore J.; Khaw, Kay Tee; Hartikainen, Anna Liisa; Hammond, Christopher J.; Gläser, Sven; Marchini, Jonathan; Kraft, Peter; Wareham, Nicholas J.; Völzke, Henry; Stricker, Bruno H.C.; Spector, Timothy D.; Probst-Hensch, Nicole M.; Jarvis, Deborah; Jarvelin, Marjo Riitta; Heckbert, Susan R.; Gudnason, Vilmundur; Boezen, H. Marike; Barr, R. Graham; Cassano, Patricia A.; Strachan, David P.; Fornage, Myriam; Hall, Ian P.; Dupuis, Josée; Tobin, Martin D.; London, Stephanie J.

In: PLoS genetics, Vol. 8, No. 12, e1003098, 01.12.2012.

Research output: Contribution to journalArticle

Hancock, DB, Artigas, MS, Gharib, SA, Henry, A, Manichaikul, A, Ramasamy, A, Loth, DW, Imboden, M, Koch, B, McArdle, WL, Smith, AV, Smolonska, J, Sood, A, Tang, W, Wilk, JB, Zhai, G, Zhao, JH, Aschard, H, Burkart, KM, Curjuric, I, Eijgelsheim, M, Elliott, P, Gu, X, Harris, TB, Janson, C, Homuth, G, Hysi, PG, Liu, JZ, Loehr, LR, Lohman, K, Loos, RJF, Manning, AK, Marciante, KD, Obeidat, M, Postma, DS, Aldrich, MC, Brusselle, GG, Chen, TH, Eiriksdottir, G, Franceschini, N, Heinrich, J, Rotter, JI, Wijmenga, C, Williams, OD, Bentley, AR, Hofman, A, Laurie, CC, Lumley, T, Morrison, AC, Joubert, BR, Rivadeneira, F, Couper, DJ, Kritchevsky, SB, Liu, Y, Wjst, M, Wain, LV, Vonk, JM, Uitterlinden, AG, Rochat, T, Rich, SS, Psaty, BM, O'Connor, GT, North, KE, Mirel, DB, Meibohm, B, Launer, LJ, Khaw, KT, Hartikainen, AL, Hammond, CJ, Gläser, S, Marchini, J, Kraft, P, Wareham, NJ, Völzke, H, Stricker, BHC, Spector, TD, Probst-Hensch, NM, Jarvis, D, Jarvelin, MR, Heckbert, SR, Gudnason, V, Boezen, HM, Barr, RG, Cassano, PA, Strachan, DP, Fornage, M, Hall, IP, Dupuis, J, Tobin, MD & London, SJ 2012, 'Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function', PLoS genetics, vol. 8, no. 12, e1003098. https://doi.org/10.1371/journal.pgen.1003098
Hancock, Dana B. ; Artigas, María Soler ; Gharib, Sina A. ; Henry, Amanda ; Manichaikul, Ani ; Ramasamy, Adaikalavan ; Loth, Daan W. ; Imboden, Medea ; Koch, Beate ; McArdle, Wendy L. ; Smith, Albert V. ; Smolonska, Joanna ; Sood, Akshay ; Tang, Wenbo ; Wilk, Jemma B. ; Zhai, Guangju ; Zhao, Jing Hua ; Aschard, Hugues ; Burkart, Kristin M. ; Curjuric, Ivan ; Eijgelsheim, Mark ; Elliott, Paul ; Gu, Xiangjun ; Harris, Tamara B. ; Janson, Christer ; Homuth, Georg ; Hysi, Pirro G. ; Liu, Jason Z. ; Loehr, Laura R. ; Lohman, Kurt ; Loos, Ruth J.F. ; Manning, Alisa K. ; Marciante, Kristin D. ; Obeidat, Ma'en ; Postma, Dirkje S. ; Aldrich, Melinda C. ; Brusselle, Guy G. ; Chen, Ting hsu ; Eiriksdottir, Gudny ; Franceschini, Nora ; Heinrich, Joachim ; Rotter, Jerome I. ; Wijmenga, Cisca ; Williams, O. Dale ; Bentley, Amy R. ; Hofman, Albert ; Laurie, Cathy C. ; Lumley, Thomas ; Morrison, Alanna C. ; Joubert, Bonnie R. ; Rivadeneira, Fernando ; Couper, David J. ; Kritchevsky, Stephen B. ; Liu, Yongmei ; Wjst, Matthias ; Wain, Louise V. ; Vonk, Judith M. ; Uitterlinden, André G. ; Rochat, Thierry ; Rich, Stephen S. ; Psaty, Bruce M. ; O'Connor, George T. ; North, Kari E. ; Mirel, Daniel B. ; Meibohm, Bernd ; Launer, Lenore J. ; Khaw, Kay Tee ; Hartikainen, Anna Liisa ; Hammond, Christopher J. ; Gläser, Sven ; Marchini, Jonathan ; Kraft, Peter ; Wareham, Nicholas J. ; Völzke, Henry ; Stricker, Bruno H.C. ; Spector, Timothy D. ; Probst-Hensch, Nicole M. ; Jarvis, Deborah ; Jarvelin, Marjo Riitta ; Heckbert, Susan R. ; Gudnason, Vilmundur ; Boezen, H. Marike ; Barr, R. Graham ; Cassano, Patricia A. ; Strachan, David P. ; Fornage, Myriam ; Hall, Ian P. ; Dupuis, Josée ; Tobin, Martin D. ; London, Stephanie J. / Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function. In: PLoS genetics. 2012 ; Vol. 8, No. 12.
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abstract = "Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA=5.00×10-11), HLA-DQB1 and HLA-DQA2 (smallest PJMA=4.35×10-9), and KCNJ2 and SOX9 (smallest PJMA=1.28×10-8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.",
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TY - JOUR

T1 - Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

AU - Hancock, Dana B.

AU - Artigas, María Soler

AU - Gharib, Sina A.

AU - Henry, Amanda

AU - Manichaikul, Ani

AU - Ramasamy, Adaikalavan

AU - Loth, Daan W.

AU - Imboden, Medea

AU - Koch, Beate

AU - McArdle, Wendy L.

AU - Smith, Albert V.

AU - Smolonska, Joanna

AU - Sood, Akshay

AU - Tang, Wenbo

AU - Wilk, Jemma B.

AU - Zhai, Guangju

AU - Zhao, Jing Hua

AU - Aschard, Hugues

AU - Burkart, Kristin M.

AU - Curjuric, Ivan

AU - Eijgelsheim, Mark

AU - Elliott, Paul

AU - Gu, Xiangjun

AU - Harris, Tamara B.

AU - Janson, Christer

AU - Homuth, Georg

AU - Hysi, Pirro G.

AU - Liu, Jason Z.

AU - Loehr, Laura R.

AU - Lohman, Kurt

AU - Loos, Ruth J.F.

AU - Manning, Alisa K.

AU - Marciante, Kristin D.

AU - Obeidat, Ma'en

AU - Postma, Dirkje S.

AU - Aldrich, Melinda C.

AU - Brusselle, Guy G.

AU - Chen, Ting hsu

AU - Eiriksdottir, Gudny

AU - Franceschini, Nora

AU - Heinrich, Joachim

AU - Rotter, Jerome I.

AU - Wijmenga, Cisca

AU - Williams, O. Dale

AU - Bentley, Amy R.

AU - Hofman, Albert

AU - Laurie, Cathy C.

AU - Lumley, Thomas

AU - Morrison, Alanna C.

AU - Joubert, Bonnie R.

AU - Rivadeneira, Fernando

AU - Couper, David J.

AU - Kritchevsky, Stephen B.

AU - Liu, Yongmei

AU - Wjst, Matthias

AU - Wain, Louise V.

AU - Vonk, Judith M.

AU - Uitterlinden, André G.

AU - Rochat, Thierry

AU - Rich, Stephen S.

AU - Psaty, Bruce M.

AU - O'Connor, George T.

AU - North, Kari E.

AU - Mirel, Daniel B.

AU - Meibohm, Bernd

AU - Launer, Lenore J.

AU - Khaw, Kay Tee

AU - Hartikainen, Anna Liisa

AU - Hammond, Christopher J.

AU - Gläser, Sven

AU - Marchini, Jonathan

AU - Kraft, Peter

AU - Wareham, Nicholas J.

AU - Völzke, Henry

AU - Stricker, Bruno H.C.

AU - Spector, Timothy D.

AU - Probst-Hensch, Nicole M.

AU - Jarvis, Deborah

AU - Jarvelin, Marjo Riitta

AU - Heckbert, Susan R.

AU - Gudnason, Vilmundur

AU - Boezen, H. Marike

AU - Barr, R. Graham

AU - Cassano, Patricia A.

AU - Strachan, David P.

AU - Fornage, Myriam

AU - Hall, Ian P.

AU - Dupuis, Josée

AU - Tobin, Martin D.

AU - London, Stephanie J.

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA=5.00×10-11), HLA-DQB1 and HLA-DQA2 (smallest PJMA=4.35×10-9), and KCNJ2 and SOX9 (smallest PJMA=1.28×10-8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

AB - Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA=5.00×10-11), HLA-DQB1 and HLA-DQA2 (smallest PJMA=4.35×10-9), and KCNJ2 and SOX9 (smallest PJMA=1.28×10-8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

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