1. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
- Author
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Shrine, Nick, Izquierdo, Abril G, Chen, Jing, Packer, Richard, Hall, Robert J, Guyatt, Anna L, Batini, Chiara, Thompson, Rebecca J, Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D, Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A, John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y, Chen, Zhengming, Li, Liming, China Kadoorie Biobank Collaborative Group, Wijnant, Sara RA, Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G, Manichaikul, Ani, Oelsner, Elizabeth C, Rich, Stephen S, Barr, R Graham, Kerr, Shona M, Vitart, Veronique, Brown, Michael R, Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M, Gharib, Sina A, Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E, Meyers, Deborah A, Bleecker, Eugene R, Gabriel, Stacey B, Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F, Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H, Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L, Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T, Thareja, Gaurav, Albagha, Omar ME, Qatar Genome Program Research (QGPR) Consortium, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O, Hiemstra, Pieter S, Slats, Annelies M, Mullin, Benjamin H, Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T, Wyss, Annah B, Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A, Joshi, Peter K, Timmers, Paul RHJ, Williams, Alexander T, Free, Robert C, Wang, Xueyang, Morrison, John L, Gilliland, Frank D, Chen, Zhanghua, Wang, Carol A, Foong, Rachel E, Harris, Sarah E, Taylor, Adele, Redmond, Paul, Cook, James P, Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T, Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H, Cox, Simon R, Pennell, Craig E, Hall, Graham L, Gauderman, W James, Brightling, Chris, Wilson, James F, Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C, Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L, Dudbridge, Frank, Silverman, Edwin K, Strachan, David P, Walters, Robin G, Morris, Andrew P, London, Stephanie J, Cho, Michael H, Wain, Louise V, Hall, Ian P, Tobin, Martin D, Shrine, Nick [0000-0003-3641-4371], Chen, Jing [0000-0003-1287-1930], Guyatt, Anna L. [0000-0003-1860-6337], Hobbs, Brian D. [0000-0001-9564-0745], Kim, Wonji [0000-0002-1249-797X], Coley, Kayesha [0000-0003-4951-6799], Chen, Zhengming [0000-0001-6423-105X], Li, Liming [0000-0001-5873-7089], Lahousse, Lies [0000-0002-3494-4363], Uitterlinden, Andre G. [0000-0002-7276-3387], Oelsner, Elizabeth C. [0000-0002-7481-9671], Rich, Stephen S. [0000-0003-3872-7793], Kerr, Shona M. [0000-0002-4137-1495], Vitart, Veronique [0000-0002-4991-3797], Jeong, Ayoung [0000-0003-1542-0756], Gharib, Sina A. [0000-0002-2480-4367], Gieger, Christian [0000-0001-6986-9554], Peters, Annette [0000-0001-6645-0985], Hu, Xiaowei [0000-0001-7804-7392], Smith, Albert Vernon [0000-0003-1942-5845], Luan, Jian’an [0000-0003-3137-6337], Langhammer, Arnulf [0000-0001-5296-6673], Willer, Cristen [0000-0001-5645-4966], Porteous, David [0000-0003-1249-6106], Smith, Blair H. [0000-0002-5362-9430], Campbell, Archie [0000-0003-0198-5078], Sofer, Tamar [0000-0001-8520-8860], Lee, Jiwon [0000-0002-4079-7494], Lim, Elise [0000-0001-8967-8464], Thareja, Gaurav [0000-0003-2277-6400], Albagha, Omar M. E. [0000-0001-5916-5983], Suhre, Karsten [0000-0001-9638-3912], Granell, Raquel [0000-0002-4890-4012], Faquih, Tariq O. [0000-0001-8026-2251], Hiemstra, Pieter S. [0000-0002-0238-5982], Hysi, Pirro [0000-0001-5752-2510], Koskela, Jukka T. [0000-0002-0154-7222], Jin, Jianping [0000-0002-3774-1609], Sikdar, Sinjini [0000-0003-1230-5162], Lee, Mikyeong [0000-0002-3036-3684], May-Wilson, Sebastian [0000-0003-2668-5717], Joshi, Peter K. [0000-0002-6361-5059], Timmers, Paul R. H. J. [0000-0002-5197-1267], Gilliland, Frank D. [0000-0002-9033-7269], Wang, Carol A. [0000-0002-4301-3974], Harris, Sarah E. [0000-0002-4941-5106], Mahajan, Anubha [0000-0001-5585-3420], Palviainen, Teemu [0000-0002-7847-8384], Kaprio, Jaakko [0000-0002-3716-2455], Pietiläinen, Kirsi H. [0000-0002-8522-1288], Cox, Simon R. [0000-0003-4036-3642], Pennell, Craig E. [0000-0002-0937-6165], Wilson, James F. [0000-0001-5751-9178], Vasankari, Tuula [0000-0002-1413-8970], Salomaa, Veikko [0000-0001-7563-5324], Timpson, Nicholas J. [0000-0002-7141-9189], Dupuis, Josée [0000-0003-2871-3603], Brumpton, Ben [0000-0002-3058-1059], Langenberg, Claudia [0000-0002-5017-7344], Weiss, Stefan [0000-0002-3553-4315], Homuth, Georg [0000-0001-6839-0605], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Morrison, Alanna C. [0000-0001-6381-4296], Rudan, Igor [0000-0001-6993-6884], Lee, Joo-Hyeon [0000-0002-7364-6422], Sayers, Ian [0000-0001-5601-5410], Rawlins, Emma L. [0000-0001-7426-3792], Dudbridge, Frank [0000-0002-8817-8908], Strachan, David P. [0000-0001-7854-1366], Walters, Robin G. [0000-0002-9179-0321], Morris, Andrew P. [0000-0002-6805-6014], London, Stephanie J. [0000-0003-4911-5290], Cho, Michael H. [0000-0002-4907-1657], Wain, Louise V. [0000-0003-4951-1867], Hall, Ian P. [0000-0001-9933-3216], Tobin, Martin D. [0000-0002-3596-7874], Apollo - University of Cambridge Repository, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of General Administration, Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Uitterlinden, Andre G [0000-0002-7276-3387], Oelsner, Elizabeth C [0000-0002-7481-9671], Rich, Stephen S [0000-0003-3872-7793], Kerr, Shona M [0000-0002-4137-1495], Gharib, Sina A [0000-0002-2480-4367], Luan, Jian'an [0000-0003-3137-6337], Smith, Blair H [0000-0002-5362-9430], Albagha, Omar ME [0000-0001-5916-5983], Faquih, Tariq O [0000-0001-8026-2251], Hiemstra, Pieter S [0000-0002-0238-5982], Koskela, Jukka T [0000-0002-0154-7222], Joshi, Peter K [0000-0002-6361-5059], Timmers, Paul RHJ [0000-0002-5197-1267], Gilliland, Frank D [0000-0002-9033-7269], Wang, Carol A [0000-0002-4301-3974], Harris, Sarah E [0000-0002-4941-5106], Pietiläinen, Kirsi H [0000-0002-8522-1288], Cox, Simon R [0000-0003-4036-3642], Pennell, Craig E [0000-0002-0937-6165], Wilson, James F [0000-0001-5751-9178], Timpson, Nicholas J [0000-0002-7141-9189], Morrison, Alanna C [0000-0001-6381-4296], Rawlins, Emma L [0000-0001-7426-3792], Strachan, David P [0000-0001-7854-1366], Walters, Robin G [0000-0002-9179-0321], Morris, Andrew P [0000-0002-6805-6014], London, Stephanie J [0000-0003-4911-5290], Cho, Michael H [0000-0002-4907-1657], Wain, Louise V [0000-0003-4951-1867], Hall, Ian P [0000-0001-9933-3216], Tobin, Martin D [0000-0002-3596-7874], Epidemiology, and Internal Medicine
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Smoking ,631/208/205/2138 ,45/43 ,article ,692/699/1785 ,Polymorphism, Single Nucleotide ,3142 Public health care science, environmental and occupational health ,Pulmonary Disease, Chronic Obstructive ,Genetics ,Humans ,1182 Biochemistry, cell and molecular biology ,Genetic Predisposition to Disease ,Lung ,Genome-Wide Association Study - Abstract
Funder: British Lung Foundation, Funder: National Institute for Health Research (NIHR), 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.
- Published
- 2023