Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

JB Wilk; NRG Shrine; LR Loehr; JH Zhao; A Manichaikul; LM Lopez; AV Smith; SR Heckbert; J Smolonska; WB Tang; Daan Loth; I Curjuric; J Hui; MH Cho; JC Latourelle; AP Henry; M Aldrich; P Bakke; TH Beaty; AR Bentley; IB Borecki; Guy Brusselle; KM Burkart; TH Chen; D Couper; JD Crapo; G Davies; J Dupuis; N Franceschini; A Gulsvik; DB Hancock; TB Harris; Bert Hofman; M Imboden; AL James; KT Khaw; Lies Lahousse; LJ (Lenore) Launer; A Litonjua; YM Liu; KK Lohman; DA Lomas; T Lumley; KD Marciante; WL McArdle; B Meibohm; AC Morrison; AW Musk; RH Myers; KE North; DS Postma; BM Psaty; SS Rich; Fernando Rivadeneira; T Rochat; JI Rotter; MS Artigas; JM Starr; André Uitterlinden; NJ Wareham; C Wijmenga; P Zanen; MA Province; EK Silverman; IJ Deary; LJ Palmer; PA Cassano; V Gudnason; RG Barr; RJF Loos; DP Strachan; SJ London; HM Boezen; N Probst-Hensch; SA Gharib; IP Hall; GT O'Connor; MD Tobin; Bruno Stricker

doi:10.1164/rccm.201202-0366OC

Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

JB Wilk, NRG Shrine, LR Loehr, JH Zhao, A Manichaikul, LM Lopez, AV Smith, SR Heckbert, J Smolonska, WB Tang, Daan Loth, I Curjuric, J Hui, MH Cho, JC Latourelle, AP Henry, M Aldrich, P Bakke, TH Beaty, AR BentleyIB Borecki, Guy Brusselle, KM Burkart, TH Chen, D Couper, JD Crapo, G Davies, J Dupuis, N Franceschini, A Gulsvik, DB Hancock, TB Harris, Bert Hofman, M Imboden, AL James, KT Khaw, Lies Lahousse, LJ (Lenore) Launer, A Litonjua, YM Liu, KK Lohman, DA Lomas, T Lumley, KD Marciante, WL McArdle, B Meibohm, AC Morrison, AW Musk, RH Myers, KE North, DS Postma, BM Psaty, SS Rich, Fernando Rivadeneira, T Rochat, JI Rotter, MS Artigas, JM Starr, André Uitterlinden, NJ Wareham, C Wijmenga, P Zanen, MA Province, EK Silverman, IJ Deary, LJ Palmer, PA Cassano, V Gudnason, RG Barr, RJF Loos, DP Strachan, SJ London, HM Boezen, N Probst-Hensch, SA Gharib, IP Hall, GT O'Connor, MD Tobin, Bruno Stricker

Research output: Contribution to journal › Article › Academic › peer-review

156 Citations (Scopus)

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-based cohorts 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 FEV1 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 statistic 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	Undefined/Unknown
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
Publication status	Published - 2012

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-03-77-02

Access to Document

10.1164/rccm.201202-0366OC

http://hdl.handle.net/1765/74960

Cite this

Wilk, JB., Shrine, NRG., Loehr, LR., Zhao, JH., Manichaikul, A., Lopez, LM., Smith, AV., Heckbert, SR., Smolonska, J., Tang, WB., Loth, D., Curjuric, I., Hui, J., Cho, MH., Latourelle, JC., Henry, AP., Aldrich, M., Bakke, P., Beaty, TH., ... Stricker, B. (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

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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-based cohorts 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 FEV1 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 statistic 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.",

author = "JB Wilk and NRG Shrine and LR Loehr and JH Zhao and A Manichaikul and LM Lopez and AV Smith and SR Heckbert and J Smolonska and WB Tang and Daan Loth and I Curjuric and J Hui and MH Cho and JC Latourelle and AP Henry and M Aldrich and P Bakke and TH Beaty and AR Bentley and IB Borecki and Guy Brusselle and KM Burkart and TH Chen and D Couper and JD Crapo and G Davies and J Dupuis and N Franceschini and A Gulsvik and DB Hancock and TB Harris and Bert Hofman and M Imboden and AL James and KT Khaw and Lies Lahousse and Launer, {LJ (Lenore)} and A Litonjua and YM Liu and KK Lohman and DA Lomas and T Lumley and KD Marciante and WL McArdle and B Meibohm and AC Morrison and AW Musk and RH Myers and KE North and DS Postma and BM Psaty and SS Rich and Fernando Rivadeneira and T Rochat and JI Rotter and MS Artigas and JM Starr and Andr{\'e} Uitterlinden and NJ Wareham and C Wijmenga and P Zanen and MA Province and EK Silverman and IJ Deary and LJ Palmer and PA Cassano and V Gudnason and RG Barr and RJF Loos and DP Strachan and SJ London and HM Boezen and N Probst-Hensch and SA Gharib and IP Hall and GT O'Connor and MD Tobin and Bruno Stricker",

year = "2012",

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

language = "Undefined/Unknown",

volume = "186",

pages = "622--632",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "7",

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Wilk, JB, Shrine, NRG, Loehr, LR, Zhao, JH, Manichaikul, A, Lopez, LM, Smith, AV, Heckbert, SR, Smolonska, J, Tang, WB, Loth, D, Curjuric, I, Hui, J, Cho, MH, Latourelle, JC, Henry, AP, Aldrich, M, Bakke, P, Beaty, TH, Bentley, AR, Borecki, IB, Brusselle, G, Burkart, KM, Chen, TH, Couper, D, Crapo, JD, Davies, G, Dupuis, J, Franceschini, N, Gulsvik, A, Hancock, DB, Harris, TB, Hofman, B, Imboden, M, James, AL, Khaw, KT, Lahousse, L, Launer, LJ, Litonjua, A, Liu, YM, 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, Artigas, MS, Starr, JM, Uitterlinden, A, 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, B 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, JB

AU - Shrine, NRG

AU - Loehr, LR

AU - Zhao, JH

AU - Manichaikul, A

AU - Lopez, LM

AU - Smith, AV

AU - Heckbert, SR

AU - Smolonska, J

AU - Tang, WB

AU - Loth, Daan

AU - Curjuric, I

AU - Hui, J

AU - Cho, MH

AU - Latourelle, JC

AU - Henry, AP

AU - Aldrich, M

AU - Bakke, P

AU - Beaty, TH

AU - Bentley, AR

AU - Borecki, IB

AU - Brusselle, Guy

AU - Burkart, KM

AU - Chen, TH

AU - Couper, D

AU - Crapo, JD

AU - Davies, G

AU - Dupuis, J

AU - Franceschini, N

AU - Gulsvik, A

AU - Hancock, DB

AU - Harris, TB

AU - Hofman, Bert

AU - Imboden, M

AU - James, AL

AU - Khaw, KT

AU - Lahousse, Lies

AU - Launer, LJ (Lenore)

AU - Litonjua, A

AU - Liu, YM

AU - Lohman, KK

AU - Lomas, DA

AU - Lumley, T

AU - Marciante, KD

AU - McArdle, WL

AU - Meibohm, B

AU - Morrison, AC

AU - Musk, AW

AU - Myers, RH

AU - North, KE

AU - Postma, DS

AU - Psaty, BM

AU - Rich, SS

AU - Rivadeneira, Fernando

AU - Rochat, T

AU - Rotter, JI

AU - Artigas, MS

AU - Starr, JM

AU - Uitterlinden, André

AU - Wareham, NJ

AU - Wijmenga, C

AU - Zanen, P

AU - Province, MA

AU - Silverman, EK

AU - Deary, IJ

AU - Palmer, LJ

AU - Cassano, PA

AU - Gudnason, V

AU - Barr, RG

AU - Loos, RJF

AU - Strachan, DP

AU - London, SJ

AU - Boezen, HM

AU - Probst-Hensch, N

AU - Gharib, SA

AU - Hall, IP

AU - O'Connor, GT

AU - Tobin, MD

AU - Stricker, Bruno

PY - 2012

Y1 - 2012

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-based cohorts 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 FEV1 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 statistic 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-based cohorts 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 FEV1 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 statistic 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.

U2 - 10.1164/rccm.201202-0366OC

DO - 10.1164/rccm.201202-0366OC

M3 - Article

C2 - 22837378

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 -