New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

Nick R G Shrine; Anna Guyatt; A Mesut Erzurumluoglu; Victoria E Jackson; Brian D Hobbs; Carl Melbourne; Chiara Batini; Katherine A. Fawcett; Kijoung Song; Phuwanat Sakornsakolpat; Xingnan Li; Ruth Boxall; Nicole F. Reeve; Ma'en  Obeidat; Jing Hua  Zhao; Matthias Wielscher; Understanding Society Scientific Group; Stefan  Weiss; Katherine Kentistou; James P. Cook; Benjamin B. Sun; Jian Zhou; Jennie Hui; Stefan Karrasch; Medea  Imboden; Sarah Harris; Jonathan Marten; Stefan Enroth; Shona Kerr; Ida Surakka; Veronique Vitart; Terho Lehtimäki; Richard J Allen; Per S Bakke; Terri H Beaty; Eugene R Bleecker; Yohan Bossé; Corry-Anke Brandsma; Zhengming Chen; James D Crapo; John Danesh; Dawn L Demeo; Frank Dudbridge; Ralf Ewert; Christian Gieger; Amund Gulsvik; Anna L. Hansell; Ke Hao; Joshua D Hoffman; John E Hokanson; Georg Homuth; Peter Joshi; Philippe Joubert; Claudia  Langenberg; Xuan Li; Liming Li; Kuang Lin; Lars Lind; Nick Locantore; Jian’an Luan; Anubha Mahajan; Joseph C. Maranville; Alison Murray; David C Nickle; Richard Packer; Margaret M.  Parker; Megan L.  Paynton; David Porteous; Dmitry Prokopenko; Dandi Qiao; Rajesh Rawal; Heiko Runz; Ian Sayers; Don D. Sin; Blair H Smith; Maria Soler Artigas; David Sparrow; Ruth Tal-Singer; Paul RHJ Timmers; Maarten van den Berge; Prescott G Woodruff; Laura M Yerges-Armstrong; Olga G. Troyanskaya; Olli .  Raitakar; Mika Kähönen; Ozren Polasek; Igor Rudan; Ian Deary; Nicole M Probst-Hensch; Holger Schulz; Alan L. James; James F Wilson; Beate Stubbe; Eleftheria Zeggini; Marjo-Riitta Jarvelin; Nick Wareham; Edwin K. Silverman; Caroline Hayward; Andrew P. Morris; Adam S Butterworth; Robert A Scott; Robin G Walters; Deborah A Meyers; Michael H Cho; David P. Strachan; Ian P. Hall; Martin D. Tobin; Louise V. Wain

doi:10.1038/s41588-018-0321-7

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

Nick R G Shrine, Anna Guyatt, A Mesut Erzurumluoglu, Victoria E Jackson, Brian D Hobbs, Carl Melbourne, Chiara Batini, Katherine A. Fawcett, Kijoung Song, Phuwanat Sakornsakolpat, Xingnan Li, Ruth Boxall, Nicole F. Reeve, Ma'en Obeidat, Jing Hua Zhao, Matthias Wielscher, Understanding Society Scientific Group, Stefan Weiss, Katherine Kentistou, James P. CookBenjamin B. Sun, Jian Zhou, Jennie Hui, Stefan Karrasch, Medea Imboden, Sarah Harris, Jonathan Marten, Stefan Enroth, Shona Kerr, Ida Surakka, Veronique Vitart, Terho Lehtimäki, Richard J Allen, Per S Bakke, Terri H Beaty, Eugene R Bleecker, Yohan Bossé, Corry-Anke Brandsma, Zhengming Chen, James D Crapo, John Danesh, Dawn L Demeo, Frank Dudbridge, Ralf Ewert, Christian Gieger, Amund Gulsvik, Anna L. Hansell, Ke Hao, Joshua D Hoffman, John E Hokanson, Georg Homuth, Peter Joshi, Philippe Joubert, Claudia Langenberg, Xuan Li, Liming Li, Kuang Lin, Lars Lind, Nick Locantore, Jian’an Luan, Anubha Mahajan, Joseph C. Maranville, Alison Murray, David C Nickle, Richard Packer, Margaret M. Parker, Megan L. Paynton, David Porteous, Dmitry Prokopenko, Dandi Qiao, Rajesh Rawal, Heiko Runz, Ian Sayers, Don D. Sin, Blair H Smith, Maria Soler Artigas, David Sparrow, Ruth Tal-Singer, Paul RHJ Timmers, Maarten van den Berge, Prescott G Woodruff, Laura M Yerges-Armstrong, Olga G. Troyanskaya, Olli . Raitakar, Mika Kähönen, Ozren Polasek, Igor Rudan, Ian Deary, Nicole M Probst-Hensch, Holger Schulz, Alan L. James, James F Wilson, Beate Stubbe, Eleftheria Zeggini, Marjo-Riitta Jarvelin, Nick Wareham, Edwin K. Silverman, Caroline Hayward, Andrew P. Morris, Adam S Butterworth, Robert A Scott, Robin G Walters, Deborah A Meyers, Michael H Cho, David P. Strachan, Ian P. Hall, Martin D. Tobin, Louise V. Wain

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

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Original language	English
Pages (from-to)	481–493
Journal	Nature Genetics
Volume	51
Early online date	25 Feb 2019
DOIs	https://doi.org/10.1038/s41588-018-0321-7
Publication status	Published - 2019

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ShrineEtalNG2018NewGeneticSignalsForLungFunction
This is an Accepted Manuscript of an article published in Nature Genetics on 25.2.2019, available online:https://www.nature.com/articles/s41588-018-0321-7
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Shrine, N. R. G., Guyatt, A., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C., Batini, C., Fawcett, K. A., Song, K., Sakornsakolpat, P., Li, X., Boxall, R., Reeve, N. F., Obeidat, M., Zhao, J. H., Wielscher, M., Understanding Society Scientific Group, Weiss, S., Kentistou, K., ... Wain, L. V. (2019). New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries. Nature Genetics, 51, 481–493. https://doi.org/10.1038/s41588-018-0321-7

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title = "New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries",

abstract = "Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.",

author = "Shrine, {Nick R G} and Anna Guyatt and Erzurumluoglu, {A Mesut} and Jackson, {Victoria E} and Hobbs, {Brian D} and Carl Melbourne and Chiara Batini and Fawcett, {Katherine A.} and Kijoung Song and Phuwanat Sakornsakolpat and Xingnan Li and Ruth Boxall and Reeve, {Nicole F.} and Ma'en Obeidat and Zhao, {Jing Hua} and Matthias Wielscher and {Understanding Society Scientific Group} and Stefan Weiss and Katherine Kentistou and Cook, {James P.} and Sun, {Benjamin B.} and Jian Zhou and Jennie Hui and Stefan Karrasch and Medea Imboden and Sarah Harris and Jonathan Marten and Stefan Enroth and Shona Kerr and Ida Surakka and Veronique Vitart and Terho Lehtim{\"a}ki and Allen, {Richard J} and Bakke, {Per S} and Beaty, {Terri H} and Bleecker, {Eugene R} and Yohan Boss{\'e} and Corry-Anke Brandsma and Zhengming Chen and Crapo, {James D} and John Danesh and Demeo, {Dawn L} and Frank Dudbridge and Ralf Ewert and Christian Gieger and Amund Gulsvik and Hansell, {Anna L.} and Ke Hao and Hoffman, {Joshua D} and Hokanson, {John E} and Georg Homuth and Peter Joshi and Philippe Joubert and Claudia Langenberg and Xuan Li and Liming Li and Kuang Lin and Lars Lind and Nick Locantore and Jian{\textquoteright}an Luan and Anubha Mahajan and Maranville, {Joseph C.} and Alison Murray and Nickle, {David C} and Richard Packer and Parker, {Margaret M.} and Paynton, {Megan L.} and David Porteous and Dmitry Prokopenko and Dandi Qiao and Rajesh Rawal and Heiko Runz and Ian Sayers and Sin, {Don D.} and Smith, {Blair H} and {Soler Artigas}, Maria and David Sparrow and Ruth Tal-Singer and Timmers, {Paul RHJ} and {van den Berge}, Maarten and Woodruff, {Prescott G} and Yerges-Armstrong, {Laura M} and Troyanskaya, {Olga G.} and Raitakar, {Olli .} and Mika K{\"a}h{\"o}nen and Ozren Polasek and Igor Rudan and Ian Deary and Probst-Hensch, {Nicole M} and Holger Schulz and James, {Alan L.} and Wilson, {James F} and Beate Stubbe and Eleftheria Zeggini and Marjo-Riitta Jarvelin and Nick Wareham and Silverman, {Edwin K.} and Caroline Hayward and Morris, {Andrew P.} and Butterworth, {Adam S} and Scott, {Robert A} and Walters, {Robin G} and Meyers, {Deborah A} and Cho, {Michael H} and Strachan, {David P.} and Hall, {Ian P.} and Tobin, {Martin D.} and Wain, {Louise V.}",

year = "2019",

doi = "10.1038/s41588-018-0321-7",

language = "English",

volume = "51",

pages = "481–493",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Shrine, NRG, Guyatt, A, Erzurumluoglu, AM, Jackson, VE, Hobbs, BD, Melbourne, C, Batini, C, Fawcett, KA, Song, K, Sakornsakolpat, P, Li, X, Boxall, R, Reeve, NF, Obeidat, M, Zhao, JH, Wielscher, M, Understanding Society Scientific Group, Weiss, S, Kentistou, K, Cook, JP, Sun, BB, Zhou, J, Hui, J, Karrasch, S, Imboden, M, Harris, S, Marten, J, Enroth, S, Kerr, S, Surakka, I, Vitart, V, Lehtimäki, T, Allen, RJ, Bakke, PS, Beaty, TH, Bleecker, ER, Bossé, Y, Brandsma, C-A, Chen, Z, Crapo, JD, Danesh, J, Demeo, DL, Dudbridge, F, Ewert, R, Gieger, C, Gulsvik, A, Hansell, AL, Hao, K, Hoffman, JD, Hokanson, JE, Homuth, G, Joshi, P, Joubert, P, Langenberg, C, Li, X, Li, L, Lin, K, Lind, L, Locantore, N, Luan, J, Mahajan, A, Maranville, JC, Murray, A, Nickle, DC, Packer, R, Parker, MM, Paynton, ML, Porteous, D, Prokopenko, D, Qiao, D, Rawal, R, Runz, H, Sayers, I, Sin, DD, Smith, BH, Soler Artigas, M, Sparrow, D, Tal-Singer, R, Timmers, PRHJ, van den Berge, M, Woodruff, PG, Yerges-Armstrong, LM, Troyanskaya, OG, Raitakar, O, Kähönen, M, Polasek, O, Rudan, I , Deary, I, Probst-Hensch, NM, Schulz, H, James, AL, Wilson, JF, Stubbe, B, Zeggini, E, Jarvelin, M-R, Wareham, N, Silverman, EK, Hayward, C, Morris, AP, Butterworth, AS, Scott, RA, Walters, RG, Meyers, DA, Cho, MH, Strachan, DP, Hall, IP, Tobin, MD & Wain, LV 2019, 'New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries', Nature Genetics, vol. 51, pp. 481–493. https://doi.org/10.1038/s41588-018-0321-7

TY - JOUR

T1 - New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

AU - Shrine, Nick R G

AU - Guyatt, Anna

AU - Erzurumluoglu, A Mesut

AU - Jackson, Victoria E

AU - Hobbs, Brian D

AU - Melbourne, Carl

AU - Batini, Chiara

AU - Fawcett, Katherine A.

AU - Song, Kijoung

AU - Sakornsakolpat, Phuwanat

AU - Li, Xingnan

AU - Boxall, Ruth

AU - Reeve, Nicole F.

AU - Obeidat, Ma'en

AU - Zhao, Jing Hua

AU - Wielscher, Matthias

AU - Understanding Society Scientific Group

AU - Weiss, Stefan

AU - Kentistou, Katherine

AU - Cook, James P.

AU - Sun, Benjamin B.

AU - Zhou, Jian

AU - Hui, Jennie

AU - Karrasch, Stefan

AU - Imboden, Medea

AU - Harris, Sarah

AU - Marten, Jonathan

AU - Enroth, Stefan

AU - Kerr, Shona

AU - Surakka, Ida

AU - Vitart, Veronique

AU - Lehtimäki, Terho

AU - Allen, Richard J

AU - Bakke, Per S

AU - Beaty, Terri H

AU - Bleecker, Eugene R

AU - Bossé, Yohan

AU - Brandsma, Corry-Anke

AU - Chen, Zhengming

AU - Crapo, James D

AU - Danesh, John

AU - Demeo, Dawn L

AU - Dudbridge, Frank

AU - Ewert, Ralf

AU - Gieger, Christian

AU - Gulsvik, Amund

AU - Hansell, Anna L.

AU - Hao, Ke

AU - Hoffman, Joshua D

AU - Hokanson, John E

AU - Homuth, Georg

AU - Joshi, Peter

AU - Joubert, Philippe

AU - Langenberg, Claudia

AU - Li, Xuan

AU - Li, Liming

AU - Lin, Kuang

AU - Lind, Lars

AU - Locantore, Nick

AU - Luan, Jian’an

AU - Mahajan, Anubha

AU - Maranville, Joseph C.

AU - Murray, Alison

AU - Nickle, David C

AU - Packer, Richard

AU - Parker, Margaret M.

AU - Paynton, Megan L.

AU - Porteous, David

AU - Prokopenko, Dmitry

AU - Qiao, Dandi

AU - Rawal, Rajesh

AU - Runz, Heiko

AU - Sayers, Ian

AU - Sin, Don D.

AU - Smith, Blair H

AU - Soler Artigas, Maria

AU - Sparrow, David

AU - Tal-Singer, Ruth

AU - Timmers, Paul RHJ

AU - van den Berge, Maarten

AU - Woodruff, Prescott G

AU - Yerges-Armstrong, Laura M

AU - Troyanskaya, Olga G.

AU - Raitakar, Olli .

AU - Kähönen, Mika

AU - Polasek, Ozren

AU - Rudan, Igor

AU - Deary, Ian

AU - Probst-Hensch, Nicole M

AU - Schulz, Holger

AU - James, Alan L.

AU - Wilson, James F

AU - Stubbe, Beate

AU - Zeggini, Eleftheria

AU - Jarvelin, Marjo-Riitta

AU - Wareham, Nick

AU - Silverman, Edwin K.

AU - Hayward, Caroline

AU - Morris, Andrew P.

AU - Butterworth, Adam S

AU - Scott, Robert A

AU - Walters, Robin G

AU - Meyers, Deborah A

AU - Cho, Michael H

AU - Strachan, David P.

AU - Hall, Ian P.

AU - Tobin, Martin D.

AU - Wain, Louise V.

PY - 2019

Y1 - 2019

N2 - Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

AB - Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

U2 - 10.1038/s41588-018-0321-7

DO - 10.1038/s41588-018-0321-7

M3 - Article

VL - 51

SP - 481

EP - 493

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

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