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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Published:2023-03
Issue:3
Volume:55
Page:410-422
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Shrine NickORCID, Izquierdo Abril G., Chen JingORCID, Packer Richard, Hall Robert J., Guyatt Anna L.ORCID, Batini Chiara, Thompson Rebecca J., Pavuluri Chandan, Malik Vidhi, Hobbs Brian D.ORCID, Moll Matthew, Kim WonjiORCID, Tal-Singer Ruth, Bakke Per, Fawcett Katherine A., John Catherine, Coley KayeshaORCID, Piga Noemi Nicole, Pozarickij Alfred, Lin Kuang, Millwood Iona Y., Chen ZhengmingORCID, Li LimingORCID, Wijnant Sara R. A., Lahousse LiesORCID, Brusselle Guy, Uitterlinden Andre G.ORCID, Manichaikul Ani, Oelsner Elizabeth C.ORCID, Rich Stephen S.ORCID, Barr R. Graham, Kerr Shona M.ORCID, Vitart VeroniqueORCID, Brown Michael R., Wielscher Matthias, Imboden Medea, Jeong AyoungORCID, Bartz Traci M., Gharib Sina A.ORCID, Flexeder Claudia, Karrasch Stefan, Gieger ChristianORCID, Peters AnnetteORCID, Stubbe Beate, Hu XiaoweiORCID, Ortega Victor E., Meyers Deborah A., Bleecker Eugene R., Gabriel Stacey B., Gupta Namrata, Smith Albert VernonORCID, Luan Jian’anORCID, Zhao Jing-Hua, Hansen Ailin F., Langhammer ArnulfORCID, Willer CristenORCID, Bhatta Laxmi, Porteous DavidORCID, Smith Blair H.ORCID, Campbell ArchieORCID, Sofer TamarORCID, Lee JiwonORCID, Daviglus Martha L., Yu Bing, Lim EliseORCID, Xu Hanfei, O’Connor George T., Thareja GauravORCID, Albagha Omar M. E.ORCID, Ismail Said I., Al-Muftah Wadha, Badji Radja, Mbarek Hamdi, Darwish Dima, Fadl Tasnim, Yasin Heba, Ennaifar Maryem, Abdellatif Rania, Alkuwari Fatima, Alvi Muhammad, Al-Sarraj Yasser, Saad Chadi, Althani Asmaa, Fethnou Eleni, Qafoud Fatima, Alkhayat Eiman, Afifi Nahla, Tomei Sara, Liu Wei, Lorenz Stephan, Syed Najeeb, Almabrazi Hakeem, Vempalli Fazulur Rehaman, Temanni Ramzi, Saqri Tariq Abu, Khatib Mohammedhusen, Hamza Mehshad, Zaid Tariq Abu, El Khouly Ahmed, Pathare Tushar, Poolat Shafeeq, Al-Ali Rashid, Al-Khodor Souhaila, Alshafai Mashael, Badii Ramin, Chouchane Lotfi, Estivill Xavier, Fakhro Khalid, Mokrab Younes, Puthen Jithesh V., Tatari Zohreh, Suhre KarstenORCID, Granell RaquelORCID, Faquih Tariq O.ORCID, Hiemstra Pieter S.ORCID, Slats Annelies M., Mullin Benjamin H., Hui Jennie, James Alan, Beilby John, Patasova Karina, Hysi PirroORCID, Koskela Jukka T.ORCID, Wyss Annah B., Jin JianpingORCID, Sikdar SinjiniORCID, Lee MikyeongORCID, May-Wilson SebastianORCID, Pirastu Nicola, Kentistou Katherine A., Joshi Peter K.ORCID, Timmers Paul R. H. J.ORCID, Williams Alexander T., Free Robert C., Wang Xueyang, Morrison John L., Gilliland Frank D.ORCID, Chen Zhanghua, Wang Carol A.ORCID, Foong Rachel E., Harris Sarah E.ORCID, Taylor Adele, Redmond Paul, Cook James P., Mahajan AnubhaORCID, Lind Lars, Palviainen TeemuORCID, Lehtimäki Terho, Raitakari Olli T., Kaprio JaakkoORCID, Rantanen Taina, Pietiläinen Kirsi H.ORCID, Cox Simon R.ORCID, Pennell Craig E.ORCID, Hall Graham L., Gauderman W. James, Brightling Chris, Wilson James F.ORCID, Vasankari TuulaORCID, Laitinen Tarja, Salomaa VeikkoORCID, Mook-Kanamori Dennis O., Timpson Nicholas J.ORCID, Zeggini Eleftheria, Dupuis JoséeORCID, Hayward Caroline, Brumpton BenORCID, Langenberg ClaudiaORCID, Weiss StefanORCID, Homuth GeorgORCID, Schmidt Carsten Oliver, Probst-Hensch Nicole, Jarvelin Marjo-RiittaORCID, Morrison Alanna C.ORCID, Polasek Ozren, Rudan IgorORCID, Lee Joo-HyeonORCID, Sayers IanORCID, Rawlins Emma L.ORCID, Dudbridge FrankORCID, Silverman Edwin K., Strachan David P.ORCID, Walters Robin G.ORCID, Morris Andrew P.ORCID, London Stephanie J.ORCID, Cho Michael H.ORCID, Wain Louise V.ORCID, Hall Ian P.ORCID, Tobin Martin D.ORCID, , , , , , ,
Abstract
AbstractLung-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 588,452 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.
Funder
BHF Centre of Research Excellence, Oxford RCUK | Medical Research Council Wellcome Trust British Lung Foundation DH | National Institute for Health Research
Publisher
Springer Science and Business Media LLC
Reference60 articles.
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