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

被引：247

作者：

Sakornsakolpat, Phuwanat ^{[1
,2
]}

Prokopenko, Dmitry ^{[1
,3
]}

Lamontagne, Maxime ^{[4
]}

Reeve, Nicola F. ^{[5
]}

Guyatt, Anna L. ^{[5
]}

Jackson, Victoria E. ^{[5
]}

Shrine, Nick ^{[5
]}

Qiao, Dandi ^{[1
]}

Bartz, Traci M. ^{[6
,7
,8
]}

Kim, Deog Kyeom ^{[9
]}

Lee, Mi Kyeong ^{[10
]}

Latourelle, Jeanne C. ^{[11
]}

Li, Xingnan ^{[12
]}

Morrow, Jarrett D. ^{[1
]}

Obeidat, Ma'en ^{[13
]}

Wyss, Annah B. ^{[10
]}

Bakke, Per ^{[14
]}

Barr, R. Graham ^{[15
,16
]}

Beaty, Terri H. ^{[17
]}

Belinsky, Steven A. ^{[18
]}

Brusselle, Guy G. ^{[19
,20
,21
]}

Crapo, James D. ^{[22
]}

de Jong, Kim ^{[23
,24
]}

DeMeo, Dawn L. ^{[1
,25
]}

Fingerlin, Tasha E. ^{[26
,27
]}

Gharib, Sina A. ^{[28
]}

Gulsvik, Amund ^{[14
]}

Hall, Ian P. ^{[29
,30
]}

Hokanson, John E. ^{[31
]}

Kim, Woo Jin ^{[32
,33
]}

Lomas, David A. ^{[34
]}

London, Stephanie J. ^{[10
]}

Meyers, Deborah A. ^{[12
]}

O'Connor, George T. ^{[35
,36
]}

Rennard, Stephen, I ^{[37
,38
]}

Schwartz, David A. ^{[39
,40
]}

Sliwinski, Pawel ^{[41
]}

Sparrow, David ^{[42
,43
]}

Strachan, David P. ^{[44
]}

Tal-Singer, Ruth ^{[45
]}

Tesfaigzi, Yohannes ^{[18
]}

Vestbo, Jorgen ^{[46
]}

Vonk, Judith M. ^{[23
,24
]}

Yim, Jae-Joon ^{[47
]}

Zhou, Xiaobo ^{[1
]}

Bosse, Yohan ^{[4
,48
]}

Manichaikul, Ani ^{[49
,50
]}

Lahousse, Lies ^{[19
,51
]}

Silverman, Edwin K. ^{[1
,25
]}

Boezen, H. Marike ^{[23
,24
]}

机构：

[1] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[2] Mahidol Univ, Dept Med, Fac Med, Siriraj Hosp, Bangkok, Thailand

[3] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Boston, MA 02114 USA

[4] Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada

[5] Univ Leicester, Genet Epidemiol Grp, Dept Hlth Sci, Leicester, Leics, England

[6] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[7] Univ Washington, Dept Med, Seattle, WA 98195 USA

[8] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[9] Seoul Natl Univ, Coll Med, SMG SNU Boramae Med Ctr, Seoul, South Korea

[10] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Raleigh, NC USA

[11] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[12] Univ Arizona, Dept Med, Tucson, AZ USA

[13] Univ British Columbia, Ctr Heart Lung Innovat, St Pauls Hosp, Vancouver, BC, Canada

[14] Univ Bergen, Dept Clin Sci, Bergen, Norway

[15] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA

[16] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA

[17] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA

[18] Lovelace Resp Res Inst, Albuquerque, NM USA

[19] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[20] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium

[21] Erasmus MC, Dept Resp Med, Rotterdam, Netherlands

[22] Natl Jewish Hlth, Div Pulm & Crit Care Med, Dept Med, Denver, CO USA

[23] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[24] Univ Groningen, Univ Med Ctr Groningen, GRIAC, Groningen, Netherlands

[25] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA

[26] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO USA

[27] Univ Colorado Denver, Dept Biostat & Informat, Aurora, CO USA

[28] Univ Washington, Computat Med Core, Ctr Lung Biol, UW Med Sleep Ctr,Dept Med, Seattle, WA 98195 USA

[29] Univ Nottingham, Div Resp Med, Queens Med Ctr, Nottingham, England

[30] Nottingham Biomed Res Ctr, Natl Inst Hlth Res, Nottingham, England

[31] Univ Colorado, Dept Epidemiol, Anschutz Med Campus, Aurora, CO USA

[32] Kangwon Natl Univ, Dept Internal Med, Sch Med, Chunchon, South Korea

[33] Kangwon Natl Univ, Environm Hlth Ctr, Chunchon, South Korea

[34] UCL, UCL Resp, London, England

[35] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA

[36] Boston Univ, Sch Med, Dept Med, Pulm Ctr, Boston, MA 02118 USA

[37] Univ Nebraska Med Ctr, Pulm Crit Care Sleep & Allergy Div, Omaha, NE USA

[38] AstraZeneca, Clin Discovery Unit, Cambridge, England

[39] Univ Colorado Denver, Dept Med, Sch Med, Aurora, CO USA

[40] Univ Colorado Denver, Sch Med, Dept Immunol, Aurora, CO USA

[41] Inst TB & Lung Dis, Dept Resp Med 2, Warsaw, Poland

[42] Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02118 USA

[43] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[44] St Georges Univ London, Populat Hlth Res Inst, London, England

[45] GlaxoSmithKline R&D, Collegeville, PA USA

[46] Univ Manchester, Sch Biol Sci, Manchester, Lancs, England

[47] Seoul Natl Univ, Coll Med, Div Pulm & Crit Care Med, Dept Internal Med, Seoul, South Korea

[48] Laval Univ, Dept Mol Med, Quebec City, PQ, Canada

[49] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[50] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

基金：

英国生物技术与生命科学研究理事会;

关键词：

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

D O I：

10.1038/s41588-018-0342-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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.

引用

页码：494 / +

页数：14

共 125 条

[1] COPD as a Systemic Disease [J].

Agusti, Alvar ;

Soriano, Joan B. .

COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, 2008, 5 (02) :133-138

[2] Telomere length in circulating leukocytes is associated with lung function and disease [J].

Albrecht, Eva ;

Sillanpaa, Elina ;

Karrasch, Stefan ;

Alves, Alexessander Couto ;

Codd, Veryan ;

Hovatta, Iiris ;

Buxton, Jessica L. ;

Nelson, Christopher P. ;

Broer, Linda ;

Hagg, Sara ;

Mangino, Massimo ;

Willemsen, Gonneke ;

Surakka, Ida ;

Ferreira, Manuel A. R. ;

Amin, Najaf ;

Oostra, Ben A. ;

Backmand, Hell M. ;

Peltonen, Markku ;

Sarna, Seppo ;

Rantanen, Taina ;

Sipila, Sarianna ;

Korhonen, Tellervo ;

Madden, Pamela A. F. ;

Gieger, Christian ;

Jorres, Rudolf A. ;

Heinrich, Joachim ;

Behr, Juergen ;

Huber, Rudolf M. ;

Peters, Annette ;

Strauch, Konstantin ;

Wichmann, H. Erich ;

Waldenberger, Melanie ;

Blakemore, Alexandra I. F. ;

de Geus, Eco J. C. ;

Nyholt, Dale R. ;

Henders, Anjali K. ;

Piirila, Paeivi L. ;

Rissanen, Aila ;

Magnusson, Patrik K. E. ;

Vinuela, Ana ;

Pietilainen, Kirsi H. ;

Martin, Nicholas G. ;

Pedersen, Nancy L. ;

Boomsma, Dorret I. ;

Spector, Tim D. ;

van Duijn, Cornelia M. ;

Kaprio, Jaakko ;

Samani, Nilesh J. ;

Jarvelin, Marjo-Riitta ;

Schulz, Holger .

EUROPEAN RESPIRATORY JOURNAL, 2014, 43 (04) :983-992

[3] Genetic association between human chitinases and lung function in COPD [J].

Aminuddin, F. ;

Akhabir, L. ;

Stefanowicz, D. ;

Pare, P. D. ;

Connett, J. E. ;

Anthonisen, N. R. ;

Fahy, J. V. ;

Seibold, M. A. ;

Burchard, E. G. ;

Eng, C. ;

Gulsvik, A. ;

Bakke, P. ;

Cho, M. H. ;

Litonjua, A. ;

Lomas, D. A. ;

Anderson, W. H. ;

Beaty, T. H. ;

Crapo, J. D. ;

Silverman, E. K. ;

Sandford, A. J. .

HUMAN GENETICS, 2012, 131 (07) :1105-1114

[4]

[Anonymous], 2018, WELLCOME OPEN RES

[5]

[Anonymous], NEW GENETIC SIGNALS

[6] A Disintegrin-like and Metalloprotease (Reprolysin-type) with Thrombospondin Type 1 Motif (ADAMTS) Superfamily: Functions and Mechanisms [J].

Apte, Suneel S. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (46) :31493-31497

[7] Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients [J].

Araya, Jun ;

Cambier, Stephanie ;

Markovics, Jennifer A. ;

Wolters, Paul ;

Jablons, David ;

Hill, Arthur ;

Finkbeiner, Walter ;

Jones, Kirk ;

Broaddus, V. Courtney ;

Sheppard, Dean ;

Barzcak, Andrea ;

Xiao, Yuanyuan ;

Erle, David J. ;

Nishimura, Stephen L. .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (11) :3551-3562

[8] LungMAP: The Molecular Atlas of Lung Development Program [J].

Ardini-Poleske, Maryanne E. ;

Clark, Robert F. ;

Ansong, Charles ;

Carson, James P. ;

Corley, Richard A. ;

Deutsch, Gail H. ;

Hagood, James S. ;

Kaminski, Naftali ;

Mariani, Thomas J. ;

Potter, Steven S. ;

Pryhuber, Gloria S. ;

Warburton, David ;

Whitsett, Jeffrey A. ;

Palmer, Scott M. ;

Ambalavanan, Namasivayam .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2017, 313 (05) :L733-L740

[9] Telomerase and idiopathic pulmonary fibrosis [J].

Armanios, Mary .

MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2012, 730 (1-2) :52-58

[10] Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation [J].

Artigas, Maria Soler ;

Wain, Louise V. ;

Miller, Suzanne ;

Kheirallah, Abdul Kader ;

Huffman, Jennifer E. ;

Ntalla, Ioanna ;

Shrine, Nick ;

Obeidat, Ma'en ;

Trochet, Holly ;

McArdle, Wendy L. ;

Alves, Alexessander Couto ;

Hui, Jennie ;

Zhao, Jing Hua ;

Joshi, Peter K. ;

Teumer, Alexander ;

Albrecht, Eva ;

Imboden, Medea ;

Rawal, Rajesh ;

Lopez, Lorna M. ;

Marten, Jonathan ;

Enroth, Stefan ;

Surakka, Ida ;

Polasek, Ozren ;

Lyytikainen, Leo-Pekka ;

Granell, Raquel ;

Hysi, Pirro G. ;

Flexeder, Claudia ;

Mahajan, Anubha ;

Beilby, John ;

Bosse, Yohan ;

Brandsma, Corry-Anke ;

Campbell, Harry ;

Gieger, Christian ;

Glaeser, Sven ;

Gonzalez, Juan R. ;

Grallert, Harald ;

Hammond, Chris J. ;

Harris, Sarah E. ;

Hartikainen, Anna-Liisa ;

Heliovaara, Markku ;

Henderson, John ;

Hocking, Lynne ;

Horikoshi, Momoko ;

Hutri-Kahonen, Nina ;

Ingelsson, Erik ;

Johansson, Asa ;

Kemp, John P. ;

Kolcic, Ivana ;

Kumar, Ashish ;

Lind, Lars .

NATURE COMMUNICATIONS, 2015, 6

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