Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Louise V Wain; Nick Shrine; María Soler Artigas; A. Mesut Erzurumluoglu; Boris Noyvert; Lara Bossini-Castillo; Ma'En Obeidat; Amanda P. Henry; Michael A. Portelli; Robert J. Hall; Charlotte K. Billington; Tracy L. Rimington; Anthony G. Fenech; Catherine John; Tineka Blake; Victoria E. Jackson; Richard J Allen; Bram P. Prins; Archie Campbell; David J. Porteous; Marjo Riitta Jarvelin; Matthias Wielscher; Alan L. James; Jennie Hui; Nicholas J. Wareham; Jing Hua Zhao; James F. Wilson; Peter K. Joshi; Beate Stubbe; Rajesh Rawal; Holger Schulz; Medea Imboden; Nicole M. Probst-Hensch; Stefan Karrasch; Christian Gieger; Ian J. Deary; Sarah E Harris; Jonathan Marten; Igor Rudan; Stefan Enroth; Ulf Gyllensten; Shona M. Kerr; Ozren Polasek; Mika Kähönen; Ida Surakka; Veronique Vitart; Caroline Hayward; Terho Lehtimäki; Olli T. Raitakari; David M. Evans; A. John Henderson; Craig E. Pennell; Carol A. Wang; Peter D. Sly; Emily S. Wan; Robert Busch; Brian D. Hobbs; Augusto A. Litonjua; David W. Sparrow; Amund Gulsvik; Per S. Bakke; James D. Crapo; Terri H. Beaty; Nadia N. Hansel; Rasika A. Mathias; Ingo Ruczinski; Kathleen C. Barnes; Yohan Bossé; Philippe Joubert; Maarten Van Den Berge; Corry Anke Brandsma; Peter D. Paré; Don D. Sin; David C. Nickle; Ke Hao; Omri Gottesman; Frederick E. Dewey; Shannon E. Bruse; David J. Carey; H. Lester Kirchner; Stefan Jonsson; Gudmar Thorleifsson; Ingileif Jonsdottir; Thorarinn Gislason; Kari Stefansson; Claudia Schurmann; Girish Nadkarni; Erwin P. Bottinger; Ruth J F Loos; Robin G. Walters; Zhengming Chen; Iona Y. Millwood; Julien Vaucher; Om P. Kurmi; Liming Li; Anna L. Hansell; Chris Brightling; Eleftheria Zeggini; Michael H. Cho; Edwin K. Silverman; Ian Sayers; Gosia Trynka; Andrew P. Morris; David P. Strachan; Ian P. Hall; Martin Tobin

doi:10.1038/ng.3787

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Louise V Wain^*, Nick Shrine, María Soler Artigas, A. Mesut Erzurumluoglu, Boris Noyvert, Lara Bossini-Castillo, Ma'En Obeidat, Amanda P. Henry, Michael A. Portelli, Robert J. Hall, Charlotte K. Billington, Tracy L. Rimington, Anthony G. Fenech, Catherine John, Tineka Blake, Victoria E. Jackson, Richard J Allen, Bram P. Prins, Archie Campbell, David J. PorteousMarjo Riitta Jarvelin, Matthias Wielscher, Alan L. James, Jennie Hui, Nicholas J. Wareham, Jing Hua Zhao, James F. Wilson, Peter K. Joshi, Beate Stubbe, Rajesh Rawal, Holger Schulz, Medea Imboden, Nicole M. Probst-Hensch, Stefan Karrasch, Christian Gieger, Ian J. Deary, Sarah E Harris, Jonathan Marten, Igor Rudan, Stefan Enroth, Ulf Gyllensten, Shona M. Kerr, Ozren Polasek, Mika Kähönen, Ida Surakka, Veronique Vitart, Caroline Hayward, Terho Lehtimäki, Olli T. Raitakari, David M. Evans, A. John Henderson, Craig E. Pennell, Carol A. Wang, Peter D. Sly, Emily S. Wan, Robert Busch, Brian D. Hobbs, Augusto A. Litonjua, David W. Sparrow, Amund Gulsvik, Per S. Bakke, James D. Crapo, Terri H. Beaty, Nadia N. Hansel, Rasika A. Mathias, Ingo Ruczinski, Kathleen C. Barnes, Yohan Bossé, Philippe Joubert, Maarten Van Den Berge, Corry Anke Brandsma, Peter D. Paré, Don D. Sin, David C. Nickle, Ke Hao, Omri Gottesman, Frederick E. Dewey, Shannon E. Bruse, David J. Carey, H. Lester Kirchner, Stefan Jonsson, Gudmar Thorleifsson, Ingileif Jonsdottir, Thorarinn Gislason, Kari Stefansson, Claudia Schurmann, Girish Nadkarni, Erwin P. Bottinger, Ruth J F Loos, Robin G. Walters, Zhengming Chen, Iona Y. Millwood, Julien Vaucher, Om P. Kurmi, Liming Li, Anna L. Hansell, Chris Brightling, Eleftheria Zeggini, Michael H. Cho, Edwin K. Silverman, Ian Sayers, Gosia Trynka, Andrew P. Morris, David P. Strachan, Ian P. Hall, Martin Tobin

^*Corresponding author for this work

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (1/46 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10 49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Original language	English
Pages (from-to)	416-425
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	3
Early online date	6 Feb 2017
DOIs	https://doi.org/10.1038/ng.3787
Publication status	Published - Mar 2017

Keywords

Lung function
COPD
Genetics

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Wain, L. V., Shrine, N., Artigas, M. S., Erzurumluoglu, A. M., Noyvert, B., Bossini-Castillo, L., Obeidat, ME., Henry, A. P., Portelli, M. A., Hall, R. J., Billington, C. K., Rimington, T. L., Fenech, A. G., John, C., Blake, T., Jackson, V. E., Allen, R. J., Prins, B. P., Campbell, A., ... Tobin, M. (2017). Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets. Nature Genetics, 49(3), 416-425. https://doi.org/10.1038/ng.3787

@article{d05cffeae45245488022bbb5d169b7e0,

title = "Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets",

abstract = "Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (1/46 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10 49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.",

keywords = "Lung function, COPD, Genetics",

author = "Wain, {Louise V} and Nick Shrine and Artigas, {Mar{\'i}a Soler} and Erzurumluoglu, {A. Mesut} and Boris Noyvert and Lara Bossini-Castillo and Ma'En Obeidat and Henry, {Amanda P.} and Portelli, {Michael A.} and Hall, {Robert J.} and Billington, {Charlotte K.} and Rimington, {Tracy L.} and Fenech, {Anthony G.} and Catherine John and Tineka Blake and Jackson, {Victoria E.} and Allen, {Richard J} and Prins, {Bram P.} and Archie Campbell and Porteous, {David J.} and Jarvelin, {Marjo Riitta} and Matthias Wielscher and James, {Alan L.} and Jennie Hui and Wareham, {Nicholas J.} and Zhao, {Jing Hua} and Wilson, {James F.} and Joshi, {Peter K.} and Beate Stubbe and Rajesh Rawal and Holger Schulz and Medea Imboden and Probst-Hensch, {Nicole M.} and Stefan Karrasch and Christian Gieger and Deary, {Ian J.} and Harris, {Sarah E} and Jonathan Marten and Igor Rudan and Stefan Enroth and Ulf Gyllensten and Kerr, {Shona M.} and Ozren Polasek and Mika K{\"a}h{\"o}nen and Ida Surakka and Veronique Vitart and Caroline Hayward and Terho Lehtim{\"a}ki and Raitakari, {Olli T.} and Evans, {David M.} and Henderson, {A. John} and Pennell, {Craig E.} and Wang, {Carol A.} and Sly, {Peter D.} and Wan, {Emily S.} and Robert Busch and Hobbs, {Brian D.} and Litonjua, {Augusto A.} and Sparrow, {David W.} and Amund Gulsvik and Bakke, {Per S.} and Crapo, {James D.} and Beaty, {Terri H.} and Hansel, {Nadia N.} and Mathias, {Rasika A.} and Ingo Ruczinski and Barnes, {Kathleen C.} and Yohan Boss{\'e} and Philippe Joubert and {Van Den Berge}, Maarten and Brandsma, {Corry Anke} and Par{\'e}, {Peter D.} and Sin, {Don D.} and Nickle, {David C.} and Ke Hao and Omri Gottesman and Dewey, {Frederick E.} and Bruse, {Shannon E.} and Carey, {David J.} and Kirchner, {H. Lester} and Stefan Jonsson and Gudmar Thorleifsson and Ingileif Jonsdottir and Thorarinn Gislason and Kari Stefansson and Claudia Schurmann and Girish Nadkarni and Bottinger, {Erwin P.} and Loos, {Ruth J F} and Walters, {Robin G.} and Zhengming Chen and Millwood, {Iona Y.} and Julien Vaucher and Kurmi, {Om P.} and Liming Li and Hansell, {Anna L.} and Chris Brightling and Eleftheria Zeggini and Cho, {Michael H.} and Silverman, {Edwin K.} and Ian Sayers and Gosia Trynka and Morris, {Andrew P.} and Strachan, {David P.} and Hall, {Ian P.} and Martin Tobin",

year = "2017",

month = mar,

doi = "10.1038/ng.3787",

language = "English",

volume = "49",

pages = "416--425",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "3",

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Wain, LV, Shrine, N, Artigas, MS, Erzurumluoglu, AM, Noyvert, B, Bossini-Castillo, L, Obeidat, ME, Henry, AP, Portelli, MA, Hall, RJ, Billington, CK, Rimington, TL, Fenech, AG, John, C, Blake, T, Jackson, VE, Allen, RJ, Prins, BP, Campbell, A, Porteous, DJ, Jarvelin, MR, Wielscher, M, James, AL, Hui, J, Wareham, NJ, Zhao, JH, Wilson, JF, Joshi, PK, Stubbe, B, Rawal, R, Schulz, H, Imboden, M, Probst-Hensch, NM, Karrasch, S, Gieger, C, Deary, IJ, Harris, SE, Marten, J, Rudan, I, Enroth, S, Gyllensten, U, Kerr, SM, Polasek, O, Kähönen, M, Surakka, I, Vitart, V, Hayward, C, Lehtimäki, T, Raitakari, OT, Evans, DM, Henderson, AJ, Pennell, CE, Wang, CA, Sly, PD, Wan, ES, Busch, R, Hobbs, BD, Litonjua, AA, Sparrow, DW, Gulsvik, A, Bakke, PS, Crapo, JD, Beaty, TH, Hansel, NN, Mathias, RA, Ruczinski, I, Barnes, KC, Bossé, Y, Joubert, P, Van Den Berge, M, Brandsma, CA, Paré, PD, Sin, DD, Nickle, DC, Hao, K, Gottesman, O, Dewey, FE, Bruse, SE, Carey, DJ, Kirchner, HL, Jonsson, S, Thorleifsson, G, Jonsdottir, I, Gislason, T, Stefansson, K, Schurmann, C, Nadkarni, G, Bottinger, EP, Loos, RJF, Walters, RG, Chen, Z, Millwood, IY, Vaucher, J, Kurmi, OP, Li, L, Hansell, AL, Brightling, C, Zeggini, E, Cho, MH, Silverman, EK, Sayers, I, Trynka, G, Morris, AP, Strachan, DP, Hall, IP & Tobin, M 2017, 'Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets', Nature Genetics, vol. 49, no. 3, pp. 416-425. https://doi.org/10.1038/ng.3787

TY - JOUR

T1 - Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

AU - Wain, Louise V

AU - Shrine, Nick

AU - Artigas, María Soler

AU - Erzurumluoglu, A. Mesut

AU - Noyvert, Boris

AU - Bossini-Castillo, Lara

AU - Obeidat, Ma'En

AU - Henry, Amanda P.

AU - Portelli, Michael A.

AU - Hall, Robert J.

AU - Billington, Charlotte K.

AU - Rimington, Tracy L.

AU - Fenech, Anthony G.

AU - John, Catherine

AU - Blake, Tineka

AU - Jackson, Victoria E.

AU - Allen, Richard J

AU - Prins, Bram P.

AU - Campbell, Archie

AU - Porteous, David J.

AU - Jarvelin, Marjo Riitta

AU - Wielscher, Matthias

AU - James, Alan L.

AU - Hui, Jennie

AU - Wareham, Nicholas J.

AU - Zhao, Jing Hua

AU - Wilson, James F.

AU - Joshi, Peter K.

AU - Stubbe, Beate

AU - Rawal, Rajesh

AU - Schulz, Holger

AU - Imboden, Medea

AU - Probst-Hensch, Nicole M.

AU - Karrasch, Stefan

AU - Gieger, Christian

AU - Deary, Ian J.

AU - Harris, Sarah E

AU - Marten, Jonathan

AU - Rudan, Igor

AU - Enroth, Stefan

AU - Gyllensten, Ulf

AU - Kerr, Shona M.

AU - Polasek, Ozren

AU - Kähönen, Mika

AU - Surakka, Ida

AU - Vitart, Veronique

AU - Hayward, Caroline

AU - Lehtimäki, Terho

AU - Raitakari, Olli T.

AU - Evans, David M.

AU - Henderson, A. John

AU - Pennell, Craig E.

AU - Wang, Carol A.

AU - Sly, Peter D.

AU - Wan, Emily S.

AU - Busch, Robert

AU - Hobbs, Brian D.

AU - Litonjua, Augusto A.

AU - Sparrow, David W.

AU - Gulsvik, Amund

AU - Bakke, Per S.

AU - Crapo, James D.

AU - Beaty, Terri H.

AU - Hansel, Nadia N.

AU - Mathias, Rasika A.

AU - Ruczinski, Ingo

AU - Barnes, Kathleen C.

AU - Bossé, Yohan

AU - Joubert, Philippe

AU - Van Den Berge, Maarten

AU - Brandsma, Corry Anke

AU - Paré, Peter D.

AU - Sin, Don D.

AU - Nickle, David C.

AU - Hao, Ke

AU - Gottesman, Omri

AU - Dewey, Frederick E.

AU - Bruse, Shannon E.

AU - Carey, David J.

AU - Kirchner, H. Lester

AU - Jonsson, Stefan

AU - Thorleifsson, Gudmar

AU - Jonsdottir, Ingileif

AU - Gislason, Thorarinn

AU - Stefansson, Kari

AU - Schurmann, Claudia

AU - Nadkarni, Girish

AU - Bottinger, Erwin P.

AU - Loos, Ruth J F

AU - Walters, Robin G.

AU - Chen, Zhengming

AU - Millwood, Iona Y.

AU - Vaucher, Julien

AU - Kurmi, Om P.

AU - Li, Liming

AU - Hansell, Anna L.

AU - Brightling, Chris

AU - Zeggini, Eleftheria

AU - Cho, Michael H.

AU - Silverman, Edwin K.

AU - Sayers, Ian

AU - Trynka, Gosia

AU - Morris, Andrew P.

AU - Strachan, David P.

AU - Hall, Ian P.

AU - Tobin, Martin

PY - 2017/3

Y1 - 2017/3

N2 - Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (1/46 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10 49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

AB - Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (1/46 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10 49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

KW - Lung function

KW - COPD

KW - Genetics

UR - http://www.scopus.com/inward/record.url?scp=85011684926&partnerID=8YFLogxK

U2 - 10.1038/ng.3787

DO - 10.1038/ng.3787

M3 - Article (Academic Journal)

C2 - 28166213

AN - SCOPUS:85011684926

SN - 1061-4036

VL - 49

SP - 416

EP - 425

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

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Keywords

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Copy of ALSPAC B2194 Henderson Lung Function Version 2

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