Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Jemma B. Wilk; Nick R.G. Shrine; Laura R. Loehr; Jing Hua Zhao; Ani Manichaikul; Lorna M. Lopez; Albert Vernon Smith; Susan R. Heckbert; Joanna Smolonska; Wenbo Tang; Daan W. Loth; Ivan Curjuric; Jennie Hui; Michael H. Cho; Jeanne C. Latourelle; Amanda P. Henry; Melinda Aldrich; Per Bakke; Terri H. Beaty; Amy R. Bentley; Ingrid B. Borecki; Guy G. Brusselle; Kristin M. Burkart; Ting Hsu Chen; David Couper; James D. Crapo; Gail Davies; Josée Dupuis; Nora Franceschini; Amund Gulsvik; Dana B. Hancock; Tamara B. Harris; Albert Hofman; Medea Imboden; Alan L. James; Kay Tee Khaw; Lies Lahousse; Lenore J. Launer; Augusto Litonjua; Yongmei Liu; Kurt K. Lohman; David A. Lomas; Thomas Lumley; Kristin D. Marciante; Wendy L. McArdle; Bernd Meibohm; Alanna C. Morrison; Arthur W. Musk; Richard H. Myers; Kari E. North; Dirkje S. Postma; Bruce M. Psaty; Stephen S. Rich; Fernando Rivadeneira; Thierry Rochat; Jerome I. Rotter; María Soler Artigas; John M. Starr; André G. Uitterlinden; Nicholas J. Wareham; Cisca Wijmenga; Pieter Zanen; Michael A. Province; Edwin K. Silverman; Ian J. Deary; Lyle J. Palmer; Patricia A. Cassano; Vilmundur Gudnason; R. Graham Barr; Ruth J.F. Loos; David P. Strachan; Stephanie J. London; H. Marike Boezen; Nicole Probst-Hensch; Sina A. Gharib; Ian P. Hall; George T. O'Connor; Martin D. Tobin; Bruno H. Stricker

doi:10.1164/rccm.201202-0366OC

Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Jemma B. Wilk, Nick R.G. Shrine, Laura R. Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M. Lopez, Albert Vernon Smith, Susan R. Heckbert, Joanna Smolonska, Wenbo Tang, Daan W. Loth, Ivan Curjuric, Jennie Hui, Michael H. Cho, Jeanne C. Latourelle, Amanda P. Henry, Melinda Aldrich, Per Bakke, Terri H. Beaty, Amy R. BentleyIngrid B. Borecki, Guy G. Brusselle, Kristin M. Burkart, Ting Hsu Chen, David Couper, James D. Crapo, Gail Davies, Josée Dupuis, Nora Franceschini, Amund Gulsvik, Dana B. Hancock, Tamara B. Harris, Albert Hofman, Medea Imboden, Alan L. James, Kay Tee Khaw, Lies Lahousse, Lenore J. Launer, Augusto Litonjua, Yongmei Liu, Kurt K. Lohman, David A. Lomas, Thomas Lumley, Kristin D. Marciante, Wendy L. McArdle, Bernd Meibohm, Alanna C. Morrison, Arthur W. Musk, Richard H. Myers, Kari E. North, Dirkje S. Postma, Bruce M. Psaty, Stephen S. Rich, Fernando Rivadeneira, Thierry Rochat, Jerome I. Rotter, María Soler Artigas, John M. Starr, André G. Uitterlinden, Nicholas J. Wareham, Cisca Wijmenga, Pieter Zanen, Michael A. Province, Edwin K. Silverman, Ian J. Deary, Lyle J. Palmer, Patricia A. Cassano, Vilmundur Gudnason, R. Graham Barr, Ruth J.F. Loos, David P. Strachan, Stephanie J. London, H. Marike Boezen, Nicole Probst-Hensch, Sina A. Gharib, Ian P. Hall, George T. O'Connor, Martin D. Tobin, Bruno H. Stricker

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153 Scopus citations

Abstract

Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-basedcohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV ₁ and its ratio to FVC (FEV₁/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV₁/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Original language	English
Pages (from-to)	622-632
Number of pages	11
Journal	American journal of respiratory and critical care medicine
Volume	186
Issue number	7
DOIs	https://doi.org/10.1164/rccm.201202-0366OC
State	Published - Oct 1 2012

Keywords

Chronic obstructive pulmonary disease
Genes
Single-nucleotide polymorphism

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Wilk, J. B., Shrine, N. R. G., Loehr, L. R., Zhao, J. H., Manichaikul, A., Lopez, L. M., Smith, A. V., Heckbert, S. R., Smolonska, J., Tang, W., Loth, D. W., Curjuric, I., Hui, J., Cho, M. H., Latourelle, J. C., Henry, A. P., Aldrich, M., Bakke, P., Beaty, T. H., ... Stricker, B. H. (2012). Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. American journal of respiratory and critical care medicine, 186(7), 622-632. https://doi.org/10.1164/rccm.201202-0366OC

@article{38f5090bb7dd4408af003db7b60af99d,

title = "Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction",

abstract = "Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-basedcohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV 1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.",

keywords = "Chronic obstructive pulmonary disease, Genes, Single-nucleotide polymorphism",

author = "Wilk, {Jemma B.} and Shrine, {Nick R.G.} and Loehr, {Laura R.} and Zhao, {Jing Hua} and Ani Manichaikul and Lopez, {Lorna M.} and Smith, {Albert Vernon} and Heckbert, {Susan R.} and Joanna Smolonska and Wenbo Tang and Loth, {Daan W.} and Ivan Curjuric and Jennie Hui and Cho, {Michael H.} and Latourelle, {Jeanne C.} and Henry, {Amanda P.} and Melinda Aldrich and Per Bakke and Beaty, {Terri H.} and Bentley, {Amy R.} and Borecki, {Ingrid B.} and Brusselle, {Guy G.} and Burkart, {Kristin M.} and Chen, {Ting Hsu} and David Couper and Crapo, {James D.} and Gail Davies and Jos{\'e}e Dupuis and Nora Franceschini and Amund Gulsvik and Hancock, {Dana B.} and Harris, {Tamara B.} and Albert Hofman and Medea Imboden and James, {Alan L.} and Khaw, {Kay Tee} and Lies Lahousse and Launer, {Lenore J.} and Augusto Litonjua and Yongmei Liu and Lohman, {Kurt K.} and Lomas, {David A.} and Thomas Lumley and Marciante, {Kristin D.} and McArdle, {Wendy L.} and Bernd Meibohm and Morrison, {Alanna C.} and Musk, {Arthur W.} and Myers, {Richard H.} and North, {Kari E.} and Postma, {Dirkje S.} and Psaty, {Bruce M.} and Rich, {Stephen S.} and Fernando Rivadeneira and Thierry Rochat and Rotter, {Jerome I.} and {Soler Artigas}, Mar{\'i}a and Starr, {John M.} and Uitterlinden, {Andr{\'e} G.} and Wareham, {Nicholas J.} and Cisca Wijmenga and Pieter Zanen and Province, {Michael A.} and Silverman, {Edwin K.} and Deary, {Ian J.} and Palmer, {Lyle J.} and Cassano, {Patricia A.} and Vilmundur Gudnason and Barr, {R. Graham} and Loos, {Ruth J.F.} and Strachan, {David P.} and London, {Stephanie J.} and Boezen, {H. Marike} and Nicole Probst-Hensch and Gharib, {Sina A.} and Hall, {Ian P.} and O'Connor, {George T.} and Tobin, {Martin D.} and Stricker, {Bruno H.}",

year = "2012",

month = oct,

day = "1",

doi = "10.1164/rccm.201202-0366OC",

language = "English",

volume = "186",

pages = "622--632",

journal = "American journal of respiratory and critical care medicine",

issn = "1073-449X",

number = "7",

}

Wilk, JB, Shrine, NRG, Loehr, LR, Zhao, JH, Manichaikul, A, Lopez, LM, Smith, AV, Heckbert, SR, Smolonska, J, Tang, W, Loth, DW, Curjuric, I, Hui, J, Cho, MH, Latourelle, JC, Henry, AP, Aldrich, M, Bakke, P, Beaty, TH, Bentley, AR, Borecki, IB, Brusselle, GG, Burkart, KM, Chen, TH, Couper, D, Crapo, JD, Davies, G, Dupuis, J, Franceschini, N, Gulsvik, A, Hancock, DB, Harris, TB, Hofman, A, Imboden, M, James, AL, Khaw, KT, Lahousse, L, Launer, LJ, Litonjua, A, Liu, Y, Lohman, KK, Lomas, DA, Lumley, T, Marciante, KD, McArdle, WL, Meibohm, B, Morrison, AC, Musk, AW, Myers, RH, North, KE, Postma, DS, Psaty, BM, Rich, SS, Rivadeneira, F, Rochat, T, Rotter, JI, Soler Artigas, M, Starr, JM, Uitterlinden, AG, Wareham, NJ, Wijmenga, C, Zanen, P, Province, MA, Silverman, EK, Deary, IJ, Palmer, LJ, Cassano, PA, Gudnason, V, Barr, RG, Loos, RJF, Strachan, DP, London, SJ, Boezen, HM, Probst-Hensch, N, Gharib, SA, Hall, IP, O'Connor, GT, Tobin, MD & Stricker, BH 2012, 'Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction', American journal of respiratory and critical care medicine, vol. 186, no. 7, pp. 622-632. https://doi.org/10.1164/rccm.201202-0366OC

TY - JOUR

T1 - Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

AU - Wilk, Jemma B.

AU - Shrine, Nick R.G.

AU - Loehr, Laura R.

AU - Zhao, Jing Hua

AU - Manichaikul, Ani

AU - Lopez, Lorna M.

AU - Smith, Albert Vernon

AU - Heckbert, Susan R.

AU - Smolonska, Joanna

AU - Tang, Wenbo

AU - Loth, Daan W.

AU - Curjuric, Ivan

AU - Hui, Jennie

AU - Cho, Michael H.

AU - Latourelle, Jeanne C.

AU - Henry, Amanda P.

AU - Aldrich, Melinda

AU - Bakke, Per

AU - Beaty, Terri H.

AU - Bentley, Amy R.

AU - Borecki, Ingrid B.

AU - Brusselle, Guy G.

AU - Burkart, Kristin M.

AU - Chen, Ting Hsu

AU - Couper, David

AU - Crapo, James D.

AU - Davies, Gail

AU - Dupuis, Josée

AU - Franceschini, Nora

AU - Gulsvik, Amund

AU - Hancock, Dana B.

AU - Harris, Tamara B.

AU - Hofman, Albert

AU - Imboden, Medea

AU - James, Alan L.

AU - Khaw, Kay Tee

AU - Lahousse, Lies

AU - Launer, Lenore J.

AU - Litonjua, Augusto

AU - Liu, Yongmei

AU - Lohman, Kurt K.

AU - Lomas, David A.

AU - Lumley, Thomas

AU - Marciante, Kristin D.

AU - McArdle, Wendy L.

AU - Meibohm, Bernd

AU - Morrison, Alanna C.

AU - Musk, Arthur W.

AU - Myers, Richard H.

AU - North, Kari E.

AU - Postma, Dirkje S.

AU - Psaty, Bruce M.

AU - Rich, Stephen S.

AU - Rivadeneira, Fernando

AU - Rochat, Thierry

AU - Rotter, Jerome I.

AU - Soler Artigas, María

AU - Starr, John M.

AU - Uitterlinden, André G.

AU - Wareham, Nicholas J.

AU - Wijmenga, Cisca

AU - Zanen, Pieter

AU - Province, Michael A.

AU - Silverman, Edwin K.

AU - Deary, Ian J.

AU - Palmer, Lyle J.

AU - Cassano, Patricia A.

AU - Gudnason, Vilmundur

AU - Barr, R. Graham

AU - Loos, Ruth J.F.

AU - Strachan, David P.

AU - London, Stephanie J.

AU - Boezen, H. Marike

AU - Probst-Hensch, Nicole

AU - Gharib, Sina A.

AU - Hall, Ian P.

AU - O'Connor, George T.

AU - Tobin, Martin D.

AU - Stricker, Bruno H.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-basedcohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV 1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

AB - Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-basedcohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV 1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

KW - Chronic obstructive pulmonary disease

KW - Genes

KW - Single-nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=84867130207&partnerID=8YFLogxK

U2 - 10.1164/rccm.201202-0366OC

DO - 10.1164/rccm.201202-0366OC

M3 - Article

C2 - 22837378

AN - SCOPUS:84867130207

SN - 1073-449X

VL - 186

SP - 622

EP - 632

JO - American journal of respiratory and critical care medicine

JF - American journal of respiratory and critical care medicine

IS - 7

ER -

Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

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