Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Phuwanat Sakornsakolpat; Dmitry Prokopenko; Maxime Lamontagne; Nicola F. Reeve; Anna L. Guyatt; Victoria E. Jackson; Nick Shrine; Dandi Qiao; Traci M. Bartz; Deog Kyeom Kim; Mi Kyeong Lee; Jeanne C. Latourelle; Xingnan Li; Jarrett D. Morrow; Ma'en Obeidat; Annah B. Wyss; Per Bakke; R. Graham Barr; Terri H. Beaty; Steven A. Belinsky; Guy G. Brusselle; James D. Crapo; Kim de Jong; Dawn L. DeMeo; Tasha E. Fingerlin; Sina A. Gharib; Amund Gulsvik; Ian P. Hall; John E. Hokanson; Woo Jin Kim; David A. Lomas; Stephanie J. London; Deborah A. Meyers; George T. O'Connor; Stephen Rennard; David A. Schwartz; Pawel Sliwinski; David Sparrow; David P. Strachan; Ruth Tal-Singer; Yohannes Tesfaigzi; Jorgen Vestbo; Judith M. Vonk; Jae-Joon Yim; Xiaobo Zhou; Yohan Bosse; Ani Manichaikul; Hester Gietema; Gerben ter Riet; Emiel F. M. Wouters; SpiroMeta Consortium; International COPD Genetics Consortium; Understanding  Society Scientific Group; Michael H. Cho

doi:10.1038/s41588-018-0342-2

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Phuwanat Sakornsakolpat, Dmitry Prokopenko, Maxime Lamontagne, Nicola F. Reeve, Anna L. Guyatt, Victoria E. Jackson, Nick Shrine, Dandi Qiao, Traci M. Bartz, Deog Kyeom Kim, Mi Kyeong Lee, Jeanne C. Latourelle, Xingnan Li, Jarrett D. Morrow, Ma'en Obeidat, Annah B. Wyss, Per Bakke, R. Graham Barr, Terri H. Beaty, Steven A. BelinskyGuy G. Brusselle, James D. Crapo, Kim de Jong, Dawn L. DeMeo, Tasha E. Fingerlin, Sina A. Gharib, Amund Gulsvik, Ian P. Hall, John E. Hokanson, Woo Jin Kim, David A. Lomas, Stephanie J. London, Deborah A. Meyers, George T. O'Connor, Stephen Rennard, David A. Schwartz, Pawel Sliwinski, David Sparrow, David P. Strachan, Ruth Tal-Singer, Yohannes Tesfaigzi, Jorgen Vestbo, Judith M. Vonk, Jae-Joon Yim, Xiaobo Zhou, Yohan Bosse, Ani Manichaikul, Hester Gietema, Gerben ter Riet, Emiel F. M. Wouters, SpiroMeta Consortium, International COPD Genetics Consortium, Understanding Society Scientific Group, Michael H. Cho^*

^*Corresponding author for this work

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

Abstract

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10 ⁻⁸; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Original language	English
Pages (from-to)	494-505
Number of pages	14
Journal	Nature Genetics
Volume	51
Issue number	3
DOIs	https://doi.org/10.1038/s41588-018-0342-2
Publication status	Published - Mar 2019

Keywords

GENOME-WIDE ASSOCIATION
ACIDIC-MAMMALIAN-CHITINASE
LD SCORE REGRESSION
LUNG-FUNCTION
EXTRACELLULAR-MATRIX
PREDOMINANT EMPHYSEMA
CONNECTIVITY MAP
ATOPIC ASTHMA
RISK LOCI
GWAS

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Sakornsakolpat, P., Prokopenko, D., Lamontagne, M., Reeve, N. F., Guyatt, A. L., Jackson, V. E., Shrine, N., Qiao, D., Bartz, T. M., Kim, D. K., Lee, M. K., Latourelle, J. C., Li, X., Morrow, J. D., Obeidat, M., Wyss, A. B., Bakke, P., Barr, R. G., Beaty, T. H., ... Cho, M. H. (2019). Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nature Genetics, 51(3), 494-505. https://doi.org/10.1038/s41588-018-0342-2

@article{500c8012b74b44d9999d2ba93c10dfbf,

title = "Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations",

abstract = "Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10 −8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.",

keywords = "GENOME-WIDE ASSOCIATION, ACIDIC-MAMMALIAN-CHITINASE, LD SCORE REGRESSION, LUNG-FUNCTION, EXTRACELLULAR-MATRIX, PREDOMINANT EMPHYSEMA, CONNECTIVITY MAP, ATOPIC ASTHMA, RISK LOCI, GWAS",

author = "Phuwanat Sakornsakolpat and Dmitry Prokopenko and Maxime Lamontagne and Reeve, {Nicola F.} and Guyatt, {Anna L.} and Jackson, {Victoria E.} and Nick Shrine and Dandi Qiao and Bartz, {Traci M.} and Kim, {Deog Kyeom} and Lee, {Mi Kyeong} and Latourelle, {Jeanne C.} and Xingnan Li and Morrow, {Jarrett D.} and Ma'en Obeidat and Wyss, {Annah B.} and Per Bakke and Barr, {R. Graham} and Beaty, {Terri H.} and Belinsky, {Steven A.} and Brusselle, {Guy G.} and Crapo, {James D.} and {de Jong}, Kim and DeMeo, {Dawn L.} and Fingerlin, {Tasha E.} and Gharib, {Sina A.} and Amund Gulsvik and Hall, {Ian P.} and Hokanson, {John E.} and Kim, {Woo Jin} and Lomas, {David A.} and London, {Stephanie J.} and Meyers, {Deborah A.} and O'Connor, {George T.} and Stephen Rennard and Schwartz, {David A.} and Pawel Sliwinski and David Sparrow and Strachan, {David P.} and Ruth Tal-Singer and Yohannes Tesfaigzi and Jorgen Vestbo and Vonk, {Judith M.} and Jae-Joon Yim and Xiaobo Zhou and Yohan Bosse and Ani Manichaikul and Hester Gietema and {ter Riet}, Gerben and Wouters, {Emiel F. M.} and {SpiroMeta Consortium} and {International COPD Genetics Consortium} and {Understanding Society Scientific Group} and Cho, {Michael H.}",

note = "Funding Information: M.H.C., E.K.S., L.V.W., M.D.T., D.A.L., and I.P.H. have received grant funding from GlaxoSmithKline (GSK). E.K.S. has received honoraria from Novartis for continuing medical education seminars and travel support from GSK. I.P.H. has received grant support from BI. R.T.-S. is an employee and shareholder of GSK. J.V. has received personal fees from GSK, Chiesi Pharmaceuticals, BI, Novartis, and AstraZeneca. D.L.D. has received grants from the National Institutes of Health for research on COPD and personal fees from Novartis. D.A.L. has received honoraria from GSK and chaired the Respiratory Therapy Area Board from 2012 to 2015. Outside the submitted work, L.L. reports expert consultation for Boehringer Ingelheim and Novartis and unrestricted grants from AstraZeneca and Chiesi. Funding Information: This work was supported by the Prince Mahidol Award Youth Program Scholarship (P. Sakornsakolpat); NHLBI R01HL084323, R01HL113264, R01HL089856, and P01HL105339 (E.K.S.); K08HL136928 (B.D.H.), the Parker B. Francis Research Opportunity Award (B.D.H.); and R01HL113264, R01HL137927, P01HL105339, and P01HL132825 (M.H.C.). This research was conducted by using the UK Biobank resource under application numbers 20915 (M.H.C.) and 648 (M.D.T.). Please refer to the Supplementary Note for full acknowledgements. Funding bodies had no role in the design of the study, the collection, analysis, or interpretation of the data, or the writing of the manuscript. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = mar,

doi = "10.1038/s41588-018-0342-2",

language = "English",

volume = "51",

pages = "494--505",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

Sakornsakolpat, P, Prokopenko, D, Lamontagne, M, Reeve, NF, Guyatt, AL, Jackson, VE, Shrine, N, Qiao, D, Bartz, TM, Kim, DK, Lee, MK, Latourelle, JC, Li, X, Morrow, JD, Obeidat, M, Wyss, AB, Bakke, P, Barr, RG, Beaty, TH, Belinsky, SA, Brusselle, GG, Crapo, JD, de Jong, K, DeMeo, DL, Fingerlin, TE, Gharib, SA, Gulsvik, A, Hall, IP, Hokanson, JE, Kim, WJ, Lomas, DA, London, SJ, Meyers, DA, O'Connor, GT, Rennard, S, Schwartz, DA, Sliwinski, P, Sparrow, D, Strachan, DP, Tal-Singer, R, Tesfaigzi, Y, Vestbo, J, Vonk, JM, Yim, J-J, Zhou, X, Bosse, Y, Manichaikul, A, Gietema, H, ter Riet, G, Wouters, EFM, SpiroMeta Consortium, International COPD Genetics Consortium, Understanding Society Scientific Group & Cho, MH 2019, 'Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations', Nature Genetics, vol. 51, no. 3, pp. 494-505. https://doi.org/10.1038/s41588-018-0342-2

TY - JOUR

T1 - Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

AU - Sakornsakolpat, Phuwanat

AU - Prokopenko, Dmitry

AU - Lamontagne, Maxime

AU - Reeve, Nicola F.

AU - Guyatt, Anna L.

AU - Jackson, Victoria E.

AU - Shrine, Nick

AU - Qiao, Dandi

AU - Bartz, Traci M.

AU - Kim, Deog Kyeom

AU - Lee, Mi Kyeong

AU - Latourelle, Jeanne C.

AU - Li, Xingnan

AU - Morrow, Jarrett D.

AU - Obeidat, Ma'en

AU - Wyss, Annah B.

AU - Bakke, Per

AU - Barr, R. Graham

AU - Beaty, Terri H.

AU - Belinsky, Steven A.

AU - Brusselle, Guy G.

AU - Crapo, James D.

AU - de Jong, Kim

AU - DeMeo, Dawn L.

AU - Fingerlin, Tasha E.

AU - Gharib, Sina A.

AU - Gulsvik, Amund

AU - Hall, Ian P.

AU - Hokanson, John E.

AU - Kim, Woo Jin

AU - Lomas, David A.

AU - London, Stephanie J.

AU - Meyers, Deborah A.

AU - O'Connor, George T.

AU - Rennard, Stephen

AU - Schwartz, David A.

AU - Sliwinski, Pawel

AU - Sparrow, David

AU - Strachan, David P.

AU - Tal-Singer, Ruth

AU - Tesfaigzi, Yohannes

AU - Vestbo, Jorgen

AU - Vonk, Judith M.

AU - Yim, Jae-Joon

AU - Zhou, Xiaobo

AU - Bosse, Yohan

AU - Manichaikul, Ani

AU - Gietema, Hester

AU - ter Riet, Gerben

AU - Wouters, Emiel F. M.

AU - SpiroMeta Consortium

AU - International COPD Genetics Consortium

AU - Understanding Society Scientific Group

AU - Cho, Michael H.

N1 - Funding Information: M.H.C., E.K.S., L.V.W., M.D.T., D.A.L., and I.P.H. have received grant funding from GlaxoSmithKline (GSK). E.K.S. has received honoraria from Novartis for continuing medical education seminars and travel support from GSK. I.P.H. has received grant support from BI. R.T.-S. is an employee and shareholder of GSK. J.V. has received personal fees from GSK, Chiesi Pharmaceuticals, BI, Novartis, and AstraZeneca. D.L.D. has received grants from the National Institutes of Health for research on COPD and personal fees from Novartis. D.A.L. has received honoraria from GSK and chaired the Respiratory Therapy Area Board from 2012 to 2015. Outside the submitted work, L.L. reports expert consultation for Boehringer Ingelheim and Novartis and unrestricted grants from AstraZeneca and Chiesi. Funding Information: This work was supported by the Prince Mahidol Award Youth Program Scholarship (P. Sakornsakolpat); NHLBI R01HL084323, R01HL113264, R01HL089856, and P01HL105339 (E.K.S.); K08HL136928 (B.D.H.), the Parker B. Francis Research Opportunity Award (B.D.H.); and R01HL113264, R01HL137927, P01HL105339, and P01HL132825 (M.H.C.). This research was conducted by using the UK Biobank resource under application numbers 20915 (M.H.C.) and 648 (M.D.T.). Please refer to the Supplementary Note for full acknowledgements. Funding bodies had no role in the design of the study, the collection, analysis, or interpretation of the data, or the writing of the manuscript. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/3

Y1 - 2019/3

N2 - Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10 −8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

AB - Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10 −8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

KW - GENOME-WIDE ASSOCIATION

KW - ACIDIC-MAMMALIAN-CHITINASE

KW - LD SCORE REGRESSION

KW - LUNG-FUNCTION

KW - EXTRACELLULAR-MATRIX

KW - PREDOMINANT EMPHYSEMA

KW - CONNECTIVITY MAP

KW - ATOPIC ASTHMA

KW - RISK LOCI

KW - GWAS

U2 - 10.1038/s41588-018-0342-2

DO - 10.1038/s41588-018-0342-2

M3 - Article

C2 - 30804561

SN - 1061-4036

VL - 51

SP - 494

EP - 505

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Abstract

Keywords

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