Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

China Kadoorie Biobank Collaborative Group; Qatar Genome Program Research (QGPR) Consortium; Nick Shrine; Abril G. Izquierdo; Jing Chen; Richard Packer; Robert J. Hall; Anna L. Guyatt; Chiara Batini; Rebecca J. Thompson; Chandan Pavuluri; Vidhi Malik; Brian D. Hobbs; Matthew Moll; Wonji Kim; Ruth Tal-Singer; Per Bakke; Katherine A. Fawcett; Catherine John; Kayesha Coley; Noemi Nicole Piga; Alfred Pozarickij; Kuang Lin; Iona Y. Millwood; Zhengming Chen; Liming Li; Sara R.A. Wijnant; Lies Lahousse; Guy Brusselle; Andre G. Uitterlinden; Ani Manichaikul; Elizabeth C. Oelsner; Stephen S. Rich; R. Graham Barr; Shona M. Kerr; Veronique Vitart; Michael R. Brown; Matthias Wielscher; Medea Imboden; Ayoung Jeong; Traci M. Bartz; Sina A. Gharib; Claudia Flexeder; Stefan Karrasch; Christian Gieger; Annette Peters; Beate Stubbe; Xiaowei Hu; Victor E. Ortega; Deborah A. Meyers; Eugene R. Bleecker; Stacey B. Gabriel; Namrata Gupta; Albert Vernon Smith; Jian'an Luan; Jing Hua Zhao; Ailin F. Hansen; Arnulf Langhammer; Cristen Willer; Laxmi Bhatta; David Porteous; Blair H. Smith; Archie Campbell; Tamar Sofer; Jiwon Lee; Martha L. Daviglus; Bing Yu; Elise Lim; Hanfei Xu; George T. O'Connor; Gaurav Thareja; Omar M.E. Albagha; Karsten Suhre; Raquel Granell; Tariq O. Faquih; Pieter S. Hiemstra; Annelies M. Slats; Benjamin H. Mullin; Jennie Hui; Alan James; John Beilby; Karina Patasova; Pirro Hysi; Jukka T. Koskela; Annah B. Wyss; Jianping Jin; Sinjini Sikdar; Mikyeong Lee; Sebastian May-Wilson; Nicola Pirastu; Katherine A. Kentistou; Peter K. Joshi; Paul R.H.J. Timmers; Alexander T. Williams; Robert C. Free; Xueyang Wang; John L. Morrison; Frank D. Gilliland; Zhanghua Chen; Carol A. Wang; Rachel E. Foong; Sarah E. Harris; Adele Taylor; Paul Redmond; James P. Cook; Anubha Mahajan; Lars Lind; Teemu Palviainen; Terho Lehtimäki; Olli T. Raitakari; Jaakko Kaprio; Taina Rantanen; Kirsi H. Pietiläinen; Simon R. Cox; Craig E. Pennell; Graham L. Hall; W. James Gauderman; Chris Brightling; James F. Wilson; Tuula Vasankari; Tarja Laitinen; Veikko Salomaa; Dennis O. Mook-Kanamori; Nicholas J. Timpson; Eleftheria Zeggini; Josée Dupuis; Caroline Hayward; Ben Brumpton; Claudia Langenberg; Stefan Weiss; Georg Homuth; Carsten Oliver Schmidt; Nicole Probst-Hensch; Marjo Riitta Jarvelin; Alanna C. Morrison; Ozren Polasek; Igor Rudan; Joo Hyeon Lee; Ian Sayers; Emma L. Rawlins; Frank Dudbridge; Edwin K. Silverman; David P. Strachan; Robin G. Walters; Andrew P. Morris; Stephanie J. London; Michael H. Cho; Louise V. Wain; Ian P. Hall; Martin D. Tobin

doi:10.1038/s41588-023-01314-0

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

China Kadoorie Biobank Collaborative Group, Qatar Genome Program Research (QGPR) Consortium, Nick Shrine, Abril G. Izquierdo, Jing Chen, Richard Packer, Robert J. Hall, Anna L. Guyatt, Chiara Batini, Rebecca J. Thompson, Chandan Pavuluri, Vidhi Malik, Brian D. Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A. Fawcett, Catherine John, Kayesha ColeyNoemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y. Millwood, Zhengming Chen, Liming Li, Sara R.A. Wijnant, Lies Lahousse, Guy Brusselle, Andre G. Uitterlinden, Ani Manichaikul, Elizabeth C. Oelsner, Stephen S. Rich, R. Graham Barr, Shona M. Kerr, Veronique Vitart, Michael R. Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M. Bartz, Sina A. Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E. Ortega, Deborah A. Meyers, Eugene R. Bleecker, Stacey B. Gabriel, Namrata Gupta, Albert Vernon Smith, Jian'an Luan, Jing Hua Zhao, Ailin F. Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H. Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L. Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T. O'Connor, Gaurav Thareja, Omar M.E. Albagha, Karsten Suhre, Raquel Granell, Tariq O. Faquih, Pieter S. Hiemstra, Annelies M. Slats, Benjamin H. Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T. Koskela, Annah B. Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A. Kentistou, Peter K. Joshi, Paul R.H.J. Timmers, Alexander T. Williams, Robert C. Free, Xueyang Wang, John L. Morrison, Frank D. Gilliland, Zhanghua Chen, Carol A. Wang, Rachel E. Foong, Sarah E. Harris, Adele Taylor, Paul Redmond, James P. Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T. Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H. Pietiläinen, Simon R. Cox, Craig E. Pennell, Graham L. Hall, W. James Gauderman, Chris Brightling, James F. Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O. Mook-Kanamori, Nicholas J. Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo Riitta Jarvelin, Alanna C. Morrison, Ozren Polasek, Igor Rudan, Joo Hyeon Lee, Ian Sayers, Emma L. Rawlins, Frank Dudbridge, Edwin K. Silverman, David P. Strachan, Robin G. Walters, Andrew P. Morris, Stephanie J. London, Michael H. Cho, Louise V. Wain, Ian P. Hall, Martin D. Tobin

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

49 Citations (Scopus)

Abstract

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Original language	English
Pages (from-to)	410-422
Number of pages	13
Journal	Nature Genetics
Volume	55
Issue number	3
DOIs	https://doi.org/10.1038/s41588-023-01314-0
Publication status	Published - Mar 2023

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China Kadoorie Biobank Collaborative Group, Qatar Genome Program Research (QGPR) Consortium, Shrine, N., Izquierdo, A. G., Chen, J., Packer, R., Hall, R. J., Guyatt, A. L., Batini, C., Thompson, R. J., Pavuluri, C., Malik, V., Hobbs, B. D., Moll, M., Kim, W., Tal-Singer, R., Bakke, P., Fawcett, K. A., John, C., ... Tobin, M. D. (2023). Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nature Genetics, 55(3), 410-422. https://doi.org/10.1038/s41588-023-01314-0

@article{9a18ceed0dbe4566b16a6ecc36713cd2,

title = "Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk",

abstract = "Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.",

keywords = "Humans, Lung, Genome-Wide Association Study, Genetic Predisposition to Disease/genetics, Pulmonary Disease, Chronic Obstructive/genetics, Smoking/adverse effects, Polymorphism, Single Nucleotide/genetics",

author = "{China Kadoorie Biobank Collaborative Group} and {Qatar Genome Program Research (QGPR) Consortium} and Nick Shrine and Izquierdo, {Abril G.} and Jing Chen and Richard Packer and Hall, {Robert J.} and Guyatt, {Anna L.} and Chiara Batini and Thompson, {Rebecca J.} and Chandan Pavuluri and Vidhi Malik and Hobbs, {Brian D.} and Matthew Moll and Wonji Kim and Ruth Tal-Singer and Per Bakke and Fawcett, {Katherine A.} and Catherine John and Kayesha Coley and Piga, {Noemi Nicole} and Alfred Pozarickij and Kuang Lin and Millwood, {Iona Y.} and Zhengming Chen and Liming Li and Wijnant, {Sara R.A.} and Lies Lahousse and Guy Brusselle and Uitterlinden, {Andre G.} and Ani Manichaikul and Oelsner, {Elizabeth C.} and Rich, {Stephen S.} and Barr, {R. Graham} and Kerr, {Shona M.} and Veronique Vitart and Brown, {Michael R.} and Matthias Wielscher and Medea Imboden and Ayoung Jeong and Bartz, {Traci M.} and Gharib, {Sina A.} and Claudia Flexeder and Stefan Karrasch and Christian Gieger and Annette Peters and Beate Stubbe and Xiaowei Hu and Ortega, {Victor E.} and Meyers, {Deborah A.} and Bleecker, {Eugene R.} and Gabriel, {Stacey B.} and Namrata Gupta and Smith, {Albert Vernon} and Jian'an Luan and Zhao, {Jing Hua} and Hansen, {Ailin F.} and Arnulf Langhammer and Cristen Willer and Laxmi Bhatta and David Porteous and Smith, {Blair H.} and Archie Campbell and Tamar Sofer and Jiwon Lee and Daviglus, {Martha L.} and Bing Yu and Elise Lim and Hanfei Xu and O'Connor, {George T.} and Gaurav Thareja and Albagha, {Omar M.E.} and Karsten Suhre and Raquel Granell and Faquih, {Tariq O.} and Hiemstra, {Pieter S.} and Slats, {Annelies M.} and Mullin, {Benjamin H.} and Jennie Hui and Alan James and John Beilby and Karina Patasova and Pirro Hysi and Koskela, {Jukka T.} and Wyss, {Annah B.} and Jianping Jin and Sinjini Sikdar and Mikyeong Lee and Sebastian May-Wilson and Nicola Pirastu and Kentistou, {Katherine A.} and Joshi, {Peter K.} and Timmers, {Paul R.H.J.} and Williams, {Alexander T.} and Free, {Robert C.} and Xueyang Wang and Morrison, {John L.} and Gilliland, {Frank D.} and Zhanghua Chen and Wang, {Carol A.} and Foong, {Rachel E.} and Harris, {Sarah E.} and Adele Taylor and Paul Redmond and Cook, {James P.} and Anubha Mahajan and Lars Lind and Teemu Palviainen and Terho Lehtim{\"a}ki and Raitakari, {Olli T.} and Jaakko Kaprio and Taina Rantanen and Pietil{\"a}inen, {Kirsi H.} and Cox, {Simon R.} and Pennell, {Craig E.} and Hall, {Graham L.} and Gauderman, {W. James} and Chris Brightling and Wilson, {James F.} and Tuula Vasankari and Tarja Laitinen and Veikko Salomaa and Mook-Kanamori, {Dennis O.} and Timpson, {Nicholas J.} and Eleftheria Zeggini and Jos{\'e}e Dupuis and Caroline Hayward and Ben Brumpton and Claudia Langenberg and Stefan Weiss and Georg Homuth and Schmidt, {Carsten Oliver} and Nicole Probst-Hensch and Jarvelin, {Marjo Riitta} and Morrison, {Alanna C.} and Ozren Polasek and Igor Rudan and Lee, {Joo Hyeon} and Ian Sayers and Rawlins, {Emma L.} and Frank Dudbridge and Silverman, {Edwin K.} and Strachan, {David P.} and Walters, {Robin G.} and Morris, {Andrew P.} and London, {Stephanie J.} and Cho, {Michael H.} and Wain, {Louise V.} and Hall, {Ian P.} and Tobin, {Martin D.}",

note = "Publisher Copyright: {\textcopyright} 2023. The Author(s).",

year = "2023",

month = mar,

doi = "10.1038/s41588-023-01314-0",

language = "English",

volume = "55",

pages = "410--422",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "3",

}

China Kadoorie Biobank Collaborative Group, Qatar Genome Program Research (QGPR) Consortium, Shrine, N, Izquierdo, AG, Chen, J, Packer, R, Hall, RJ, Guyatt, AL, Batini, C, Thompson, RJ, Pavuluri, C, Malik, V, Hobbs, BD, Moll, M, Kim, W, Tal-Singer, R, Bakke, P, Fawcett, KA, John, C, Coley, K, Piga, NN, Pozarickij, A, Lin, K, Millwood, IY, Chen, Z, Li, L, Wijnant, SRA, Lahousse, L, Brusselle, G, Uitterlinden, AG, Manichaikul, A, Oelsner, EC, Rich, SS, Barr, RG, Kerr, SM, Vitart, V, Brown, MR, Wielscher, M, Imboden, M, Jeong, A, Bartz, TM, Gharib, SA, Flexeder, C, Karrasch, S, Gieger, C, Peters, A, Stubbe, B, Hu, X, Ortega, VE, Meyers, DA, Bleecker, ER, Gabriel, SB, Gupta, N, Smith, AV, Luan, J, Zhao, JH, Hansen, AF, Langhammer, A, Willer, C, Bhatta, L, Porteous, D, Smith, BH, Campbell, A, Sofer, T, Lee, J, Daviglus, ML, Yu, B, Lim, E, Xu, H, O'Connor, GT, Thareja, G, Albagha, OME, Suhre, K, Granell, R, Faquih, TO, Hiemstra, PS, Slats, AM, Mullin, BH , Hui, J , James, A , Beilby, J, Patasova, K, Hysi, P, Koskela, JT, Wyss, AB, Jin, J, Sikdar, S, Lee, M, May-Wilson, S, Pirastu, N, Kentistou, KA, Joshi, PK, Timmers, PRHJ, Williams, AT, Free, RC, Wang, X, Morrison, JL, Gilliland, FD, Chen, Z, Wang, CA, Foong, RE, Harris, SE, Taylor, A, Redmond, P, Cook, JP, Mahajan, A, Lind, L, Palviainen, T, Lehtimäki, T, Raitakari, OT, Kaprio, J, Rantanen, T, Pietiläinen, KH, Cox, SR, Pennell, CE, Hall, GL, Gauderman, WJ, Brightling, C, Wilson, JF, Vasankari, T, Laitinen, T, Salomaa, V, Mook-Kanamori, DO, Timpson, NJ, Zeggini, E, Dupuis, J, Hayward, C, Brumpton, B, Langenberg, C, Weiss, S, Homuth, G, Schmidt, CO, Probst-Hensch, N, Jarvelin, MR, Morrison, AC, Polasek, O, Rudan, I, Lee, JH, Sayers, I, Rawlins, EL, Dudbridge, F, Silverman, EK, Strachan, DP, Walters, RG, Morris, AP, London, SJ, Cho, MH, Wain, LV, Hall, IP & Tobin, MD 2023, 'Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk', Nature Genetics, vol. 55, no. 3, pp. 410-422. https://doi.org/10.1038/s41588-023-01314-0

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. / China Kadoorie Biobank Collaborative Group; Qatar Genome Program Research (QGPR) Consortium; Shrine, Nick et al.
In: Nature Genetics, Vol. 55, No. 3, 03.2023, p. 410-422.

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

TY - JOUR

T1 - Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

AU - China Kadoorie Biobank Collaborative Group

AU - Qatar Genome Program Research (QGPR) Consortium

AU - Shrine, Nick

AU - Izquierdo, Abril G.

AU - Chen, Jing

AU - Packer, Richard

AU - Hall, Robert J.

AU - Guyatt, Anna L.

AU - Batini, Chiara

AU - Thompson, Rebecca J.

AU - Pavuluri, Chandan

AU - Malik, Vidhi

AU - Hobbs, Brian D.

AU - Moll, Matthew

AU - Kim, Wonji

AU - Tal-Singer, Ruth

AU - Bakke, Per

AU - Fawcett, Katherine A.

AU - John, Catherine

AU - Coley, Kayesha

AU - Piga, Noemi Nicole

AU - Pozarickij, Alfred

AU - Lin, Kuang

AU - Millwood, Iona Y.

AU - Chen, Zhengming

AU - Li, Liming

AU - Wijnant, Sara R.A.

AU - Lahousse, Lies

AU - Brusselle, Guy

AU - Uitterlinden, Andre G.

AU - Manichaikul, Ani

AU - Oelsner, Elizabeth C.

AU - Rich, Stephen S.

AU - Barr, R. Graham

AU - Kerr, Shona M.

AU - Vitart, Veronique

AU - Brown, Michael R.

AU - Wielscher, Matthias

AU - Imboden, Medea

AU - Jeong, Ayoung

AU - Bartz, Traci M.

AU - Gharib, Sina A.

AU - Flexeder, Claudia

AU - Karrasch, Stefan

AU - Gieger, Christian

AU - Peters, Annette

AU - Stubbe, Beate

AU - Hu, Xiaowei

AU - Ortega, Victor E.

AU - Meyers, Deborah A.

AU - Bleecker, Eugene R.

AU - Gabriel, Stacey B.

AU - Gupta, Namrata

AU - Smith, Albert Vernon

AU - Luan, Jian'an

AU - Zhao, Jing Hua

AU - Hansen, Ailin F.

AU - Langhammer, Arnulf

AU - Willer, Cristen

AU - Bhatta, Laxmi

AU - Porteous, David

AU - Smith, Blair H.

AU - Campbell, Archie

AU - Sofer, Tamar

AU - Lee, Jiwon

AU - Daviglus, Martha L.

AU - Yu, Bing

AU - Lim, Elise

AU - Xu, Hanfei

AU - O'Connor, George T.

AU - Thareja, Gaurav

AU - Albagha, Omar M.E.

AU - Suhre, Karsten

AU - Granell, Raquel

AU - Faquih, Tariq O.

AU - Hiemstra, Pieter S.

AU - Slats, Annelies M.

AU - Mullin, Benjamin H.

AU - Hui, Jennie

AU - James, Alan

AU - Beilby, John

AU - Patasova, Karina

AU - Hysi, Pirro

AU - Koskela, Jukka T.

AU - Wyss, Annah B.

AU - Jin, Jianping

AU - Sikdar, Sinjini

AU - Lee, Mikyeong

AU - May-Wilson, Sebastian

AU - Pirastu, Nicola

AU - Kentistou, Katherine A.

AU - Joshi, Peter K.

AU - Timmers, Paul R.H.J.

AU - Williams, Alexander T.

AU - Free, Robert C.

AU - Wang, Xueyang

AU - Morrison, John L.

AU - Gilliland, Frank D.

AU - Chen, Zhanghua

AU - Wang, Carol A.

AU - Foong, Rachel E.

AU - Harris, Sarah E.

AU - Taylor, Adele

AU - Redmond, Paul

AU - Cook, James P.

AU - Mahajan, Anubha

AU - Lind, Lars

AU - Palviainen, Teemu

AU - Lehtimäki, Terho

AU - Raitakari, Olli T.

AU - Kaprio, Jaakko

AU - Rantanen, Taina

AU - Pietiläinen, Kirsi H.

AU - Cox, Simon R.

AU - Pennell, Craig E.

AU - Hall, Graham L.

AU - Gauderman, W. James

AU - Brightling, Chris

AU - Wilson, James F.

AU - Vasankari, Tuula

AU - Laitinen, Tarja

AU - Salomaa, Veikko

AU - Mook-Kanamori, Dennis O.

AU - Timpson, Nicholas J.

AU - Zeggini, Eleftheria

AU - Dupuis, Josée

AU - Hayward, Caroline

AU - Brumpton, Ben

AU - Langenberg, Claudia

AU - Weiss, Stefan

AU - Homuth, Georg

AU - Schmidt, Carsten Oliver

AU - Probst-Hensch, Nicole

AU - Jarvelin, Marjo Riitta

AU - Morrison, Alanna C.

AU - Polasek, Ozren

AU - Rudan, Igor

AU - Lee, Joo Hyeon

AU - Sayers, Ian

AU - Rawlins, Emma L.

AU - Dudbridge, Frank

AU - Silverman, Edwin K.

AU - Strachan, David P.

AU - Walters, Robin G.

AU - Morris, Andrew P.

AU - London, Stephanie J.

AU - Cho, Michael H.

AU - Wain, Louise V.

AU - Hall, Ian P.

AU - Tobin, Martin D.

PY - 2023/3

Y1 - 2023/3

N2 - Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

AB - Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

KW - Humans

KW - Lung

KW - Genome-Wide Association Study

KW - Genetic Predisposition to Disease/genetics

KW - Pulmonary Disease, Chronic Obstructive/genetics

KW - Smoking/adverse effects

KW - Polymorphism, Single Nucleotide/genetics

UR - http://www.scopus.com/inward/record.url?scp=85150122193&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01314-0

DO - 10.1038/s41588-023-01314-0

M3 - Article

C2 - 36914875

SN - 1061-4036

VL - 55

SP - 410

EP - 422

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

China Kadoorie Biobank Collaborative Group, Qatar Genome Program Research (QGPR) Consortium, Shrine N, Izquierdo AG, Chen J, Packer R et al. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nature Genetics. 2023 Mar;55(3):410-422. doi: 10.1038/s41588-023-01314-0

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

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