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 Curjuric; Mark 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

doi:10.1371/journal.pgen.1003098

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

Bristol Medical School (PHS)

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122 Citations (Scopus)

Abstract

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/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 FEV(1) and FEV(1)/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 P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) 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 language	English
Pages (from-to)	e1003098
Journal	PLoS Genetics
Volume	8
Issue number	12
DOIs	https://doi.org/10.1371/journal.pgen.1003098
Publication status	Published - 2012

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Hancock, D. B., Artigas, M. S., Gharib, S. A., Henry, A., Manichaikul, A., Ramasamy, A., Loth, D. W., Imboden, M., Koch, B., McArdle, W. L., Smith, A. V., Smolonska, J., Sood, A., Tang, W., Wilk, J. B., Zhai, G., Zhao, J. H., Aschard, H., Burkart, K. M., ... 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

@article{fda1acb2f3cc4669b3a4c19e351f5626,

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

abstract = "Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/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 FEV(1) and FEV(1)/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 P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) 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.",

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

year = "2012",

doi = "10.1371/journal.pgen.1003098",

language = "English",

volume = "8",

pages = "e1003098",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science",

number = "12",

}

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, T-H, 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, K-T, Hartikainen, A-L, Hammond, CJ, Gläser, S, Marchini, J, Kraft, P, Wareham, NJ, Völzke, H, Stricker, BHC, Spector, TD, Probst-Hensch, NM, Jarvis, D, Jarvelin, M-R, 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, pp. e1003098. https://doi.org/10.1371/journal.pgen.1003098

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

Y1 - 2012

N2 - Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/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 FEV(1) and FEV(1)/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 P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) 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 (FEV(1)), and its ratio to forced vital capacity (FEV(1)/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 FEV(1) and FEV(1)/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 P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) 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.

U2 - 10.1371/journal.pgen.1003098

DO - 10.1371/journal.pgen.1003098

M3 - Article (Academic Journal)

C2 - 23284291

SN - 1553-7404

VL - 8

SP - e1003098

JO - PLoS Genetics

JF - PLoS Genetics

IS - 12

ER -

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

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