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

Understanding Society Scientific Group; 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; Andrew P Morris

doi:10.1038/ng.3787

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

Understanding Society Scientific Group, 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 CampbellDavid 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, Andrew P Morris

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

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 (∼6 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	9
Journal	Nature Genetics
Volume	49
Issue number	3
DOIs	https://doi.org/10.1038/ng.3787
Publication status	Published - 6 Feb 2017

Keywords / Materials (for Non-textual outputs)

lung function
Chronic obstructive pulmonary disease
Lungs
Pulmonary disease
Heart
heart disease
GWAS

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10.1038/ng.3787

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targetsAccepted author manuscript, 92.7 KB

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Understanding Society Scientific Group, Wain, L. V., Shrine, N., Artigas, M. S., Erzurumluoglu, A. M., Noyvert, B., Bossini-Castillo, L., Obeidat, M., 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., ... Morris, A. P. (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

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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 (∼6 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, Chronic obstructive pulmonary disease, Lungs, Pulmonary disease, Heart, heart disease, GWAS",

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month = feb,

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doi = "10.1038/ng.3787",

language = "English",

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Understanding Society Scientific Group, Wain, LV, Shrine, N, Artigas, MS, Erzurumluoglu, AM, Noyvert, B, Bossini-Castillo, L, Obeidat, M, 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, M-R, 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 & Morris, AP 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

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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

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AU - Fenech, Anthony G

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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 - Morris, Andrew P

PY - 2017/2/6

Y1 - 2017/2/6

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 (∼6 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 (∼6 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 - Chronic obstructive pulmonary disease

KW - Lungs

KW - Pulmonary disease

KW - Heart

KW - heart disease

KW - GWAS

UR - https://www.nature.com/article-assets/npg/ng/journal/v49/n3/extref/ng.3787-S1.pdf

U2 - 10.1038/ng.3787

DO - 10.1038/ng.3787

M3 - Article

C2 - 28166213

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

Abstract

Keywords / Materials (for Non-textual outputs)

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RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

A genome wide association study of non pathological cognitive ageing

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

Abstract

Keywords / Materials (for Non-textual outputs)

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Other files and links

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Projects

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

A genome wide association study of non pathological cognitive ageing

Cite this