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

Understanding Society Scientific Group

doi:10.1038/s41588-018-0321-7

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

Understanding Society Scientific Group

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

254 Citations (Scopus)

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (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 populations. Furthermore, the combined effect of these variants showed generalizability 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
Number of pages	13
Journal	Nature Genetics
Volume	51
Issue number	3
Early online date	25 Feb 2019
DOIs	https://doi.org/10.1038/s41588-018-0321-7
Publication status	Published - Mar 2019

Bibliographical note

This research has been conducted using the UK Biobank Resource under applications 648, 4892 and 26041. L. Wain holds a GSK/British Lung Foundation Chair in Respiratory Research. M. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M. Tobin and L. Wain have been supported by the Medical Research Council (MRC) (MR/N011317/1). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. I.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details for other co-authors and contributing studies (including the SpiroMeta consortium) are in the Supplementary Note.

Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0321-7, published online 25 February 2019.

Keywords

Aged
Aged, 80 and over
Case-Control Studies
Female
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study/methods
Humans
Lung/physiopathology
Male
Middle Aged
Polymorphism, Single Nucleotide/genetics
Pulmonary Disease, Chronic Obstructive/genetics
Risk Factors
Smoking/genetics
GWAS
VARIANTS
LOCI
HERITABILITY
GENOME-WIDE ASSOCIATION
COPD

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

abstract = "Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (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 populations. Furthermore, the combined effect of these variants showed generalizability 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.",

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author = "Nick Shrine and Guyatt, {Anna L} and Erzurumluoglu, {A Mesut} and Jackson, {Victoria E} and Hobbs, {Brian D} and Melbourne, {Carl A} and Chiara Batini and Fawcett, {Katherine A} and Kijoung Song and Phuwanat Sakornsakolpat and Xingnan Li and Ruth Boxall and Reeve, {Nicola F} and Ma'en Obeidat and Zhao, {Jing Hua} and Matthias Wielscher and Stefan Weiss and Kentistou, {Katherine A} and Cook, {James P} and Sun, {Benjamin B} and Jian Zhou and Jennie Hui and Stefan Karrasch and Medea Imboden and Harris, {Sarah E} and Jonathan Marten and Stefan Enroth and Kerr, {Shona M} 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 Alison Murray and {Understanding Society Scientific Group}",

note = "This research has been conducted using the UK Biobank Resource under applications 648, 4892 and 26041. L. Wain holds a GSK/British Lung Foundation Chair in Respiratory Research. M. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M. Tobin and L. Wain have been supported by the Medical Research Council (MRC) (MR/N011317/1). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. I.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details for other co-authors and contributing studies (including the SpiroMeta consortium) are in the Supplementary Note. Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0321-7, published online 25 February 2019.",

year = "2019",

month = mar,

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

language = "English",

volume = "51",

pages = "481--493",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

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TY - JOUR

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

AU - Shrine, Nick

AU - Guyatt, Anna L

AU - Erzurumluoglu, A Mesut

AU - Jackson, Victoria E

AU - Hobbs, Brian D

AU - Melbourne, Carl A

AU - Batini, Chiara

AU - Fawcett, Katherine A

AU - Song, Kijoung

AU - Sakornsakolpat, Phuwanat

AU - Li, Xingnan

AU - Boxall, Ruth

AU - Reeve, Nicola F

AU - Obeidat, Ma'en

AU - Zhao, Jing Hua

AU - Wielscher, Matthias

AU - Weiss, Stefan

AU - Kentistou, Katherine A

AU - Cook, James P

AU - Sun, Benjamin B

AU - Zhou, Jian

AU - Hui, Jennie

AU - Karrasch, Stefan

AU - Imboden, Medea

AU - Harris, Sarah E

AU - Marten, Jonathan

AU - Enroth, Stefan

AU - Kerr, Shona M

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 - Murray, Alison

AU - Understanding Society Scientific Group

N1 - This research has been conducted using the UK Biobank Resource under applications 648, 4892 and 26041. L. Wain holds a GSK/British Lung Foundation Chair in Respiratory Research. M. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M. Tobin and L. Wain have been supported by the Medical Research Council (MRC) (MR/N011317/1). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. I.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details for other co-authors and contributing studies (including the SpiroMeta consortium) are in the Supplementary Note. Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0321-7, published online 25 February 2019.

PY - 2019/3

Y1 - 2019/3

N2 - Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (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 populations. Furthermore, the combined effect of these variants showed generalizability 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 chronic obstructive pulmonary disease (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 populations. Furthermore, the combined effect of these variants showed generalizability 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.

KW - Aged

KW - Aged, 80 and over

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Lung/physiopathology

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide/genetics

KW - Pulmonary Disease, Chronic Obstructive/genetics

KW - Risk Factors

KW - Smoking/genetics

KW - GWAS

KW - VARIANTS

KW - LOCI

KW - HERITABILITY

KW - GENOME-WIDE ASSOCIATION

KW - COPD

UR - https://doi.org/10.1038/s41588-019-0438-3

UR - http://www.mendeley.com/research/new-genetic-signals-lung-function-highlight-pathways-chronic-obstructive-pulmonary-disease-associati

U2 - 10.1038/s41588-018-0321-7

DO - 10.1038/s41588-018-0321-7

M3 - Article

C2 - 30804560

SN - 1061-4036

VL - 51

SP - 481

EP - 493

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

Abstract

Bibliographical note

Keywords

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