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

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

<p dir="ltr">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 588,452 participants, we identified 1,020 independent associat...

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Main Author: Nick Shrine (220391) (author)
Other Authors: Abril G. Izquierdo (14864251) (author), Jing Chen (4762) (author), Richard Packer (7522310) (author), Robert J. Hall (3076932) (author), Anna L. Guyatt (8609598) (author), Chiara Batini (3259911) (author), Rebecca J. Thompson (10897770) (author), Chandan Pavuluri (14864254) (author), Vidhi Malik (10430991) (author), Brian D. Hobbs (5118383) (author), Matthew Moll (8467623) (author), Wonji Kim (829493) (author), Ruth Tal-Singer (164946) (author), Per Bakke (164964) (author), Katherine A. Fawcett (3107652) (author), Catherine John (7757003) (author), Kayesha Coley (14133258) (author), Noemi Nicole Piga (14333214) (author), Alfred Pozarickij (14134748) (author), Kuang Lin (9910) (author), Iona Y. Millwood (11446853) (author), Zhengming Chen (385056) (author), Liming Li (229765) (author), China Kadoorie Biobank Collaborative Group (12776024) (author), Sara R. A. Wijnant (14864257) (author), Lies Lahousse (548910) (author), Guy Brusselle (335931) (author), Andre G. Uitterlinden (11049924) (author), Ani Manichaikul (110134) (author), Elizabeth C. Oelsner (7803734) (author), Stephen S. Rich (7634141) (author), R. Graham Barr (7634171) (author), Shona M. Kerr (7956728) (author), Veronique Vitart (149854) (author), Michael R. Brown (5410775) (author), Matthias Wielscher (3848728) (author), Medea Imboden (110145) (author), Ayoung Jeong (5676902) (author), Traci M. Bartz (3944510) (author), Sina A. Gharib (63265) (author), Claudia Flexeder (412834) (author), Stefan Karrasch (412837) (author), Christian Gieger (87555) (author), Annette Peters (62601) (author), Beate Stubbe (8950580) (author), Xiaowei Hu (1936294) (author), Victor E. Ortega (7782260) (author), Deborah A. Meyers (7782272) (author), Eugene R. Bleecker (7782269) (author), Stacey B. Gabriel (15032310) (author), Namrata Gupta (229166) (author), Albert Vernon Smith (7718669) (author), Jian’an Luan (3368636) (author), Jing-Hua Zhao (6738632) (author), Ailin F. Hansen (19520923) (author), Arnulf Langhammer (75692) (author), Cristen Willer (189988) (author), Laxmi Bhatta (389055) (author), David Porteous (150029) (author), Blair H. Smith (7726100) (author), Archie Campbell (669891) (author), Tamar Sofer (3987383) (author), Jiwon Lee (1437691) (author), Martha L. Daviglus (217211) (author), Bing Yu (237109) (author), Elise Lim (3965699) (author), Hanfei Xu (7782245) (author), George T. O’Connor (7782248) (author), Gaurav Thareja (459188) (author), Omar M. E. Albagha (11704871) (author), The Qatar Genome Program Research (QGPR) Consortium (14157276) (author), Said I. Ismail (11721428) (author), Wadha Al-Muftah (14152551) (author), Radja Badji (14152548) (author), Hamdi Mbarek (134997) (author), Dima Darwish (14152545) (author), Tasnim Fadl (14152533) (author), Heba Yasin (14152542) (author), Maryem Ennaifar (14778556) (author), Rania Abdellatif (18589450) (author), Fatima Alkuwari (14778562) (author), Muhammad Alvi (4831311) (author), Yasser Al-Sarraj (11721425) (author), Chadi Saad (5369351) (author), Asmaa Althani (499903) (author), Biobank and Sample Preparation (14778622) (author), Eleni Fethnou (14778568) (author), Fatima Qafoud (14778571) (author), Eiman Alkhayat (14778574) (author), Nahla Afifi (193245) (author), Sequencing and Genotyping group (14778625) (author), Sara Tomei (3441323) (author), Wei Liu (20030) (author), Stephan Lorenz (466378) (author), Applied Bioinformatics Core (14778628) (author), Najeeb Syed (12561967) (author), Hakeem Almabrazi (6561371) (author), Fazulur Rehaman Vempalli (14778577) (author), Ramzi Temanni (671528) (author), Data Management and Computing Infrastructure group (14778631) (author), Tariq Abu Saqri (14778580) (author), Mohammedhusen Khatib (14778583) (author), Mehshad Hamza (14778586) (author), Tariq Abu Zaid (14778589) (author), Ahmed El Khouly (14778592) (author), Tushar Pathare (14778595) (author), Shafeeq Poolat (14778598) (author), Rashid Al-Ali (846229) (author), Consortium Lead Principal Investigators (14778634) (author), Souhaila Al-Khodor (247417) (author), Mashael Alshafai (14778607) (author), Ramin Badii (491543) (author), Lotfi Chouchane (61840) (author), Xavier Estivill (23803) (author), Khalid Fakhro (3441305) (author), Younes Mokrab (6367) (author), Jithesh V. Puthen (14778610) (author), Zohreh Tatari (14778613) (author), Karsten Suhre (67967) (author), Raquel Granell (123318) (author), Tariq O. Faquih (19520926) (author), Pieter S. Hiemstra (7392584) (author), Annelies M. Slats (19520929) (author), Benjamin H. Mullin (7774733) (author), Jennie Hui (220409) (author), Alan James (528475) (author), John Beilby (405654) (author), Karina Patasova (13844399) (author), Pirro Hysi (247490) (author), Jukka T. Koskela (19520932) (author), Annah B. Wyss (7736168) (author), Jianping Jin (69636) (author), Sinjini Sikdar (3711295) (author), Mikyeong Lee (11878176) (author), Sebastian May-Wilson (19520935) (author), Nicola Pirastu (149842) (author), Katherine A. Kentistou (12733703) (author), Peter K. Joshi (7693739) (author), Paul R. H. J. Timmers (13992132) (author), Alexander T. Williams (19520938) (author), Robert C. Free (7165082) (author), Xueyang Wang (6813818) (author), John L. Morrison (19520941) (author), Frank D. Gilliland (7400321) (author), Zhanghua Chen (521433) (author), Carol A. Wang (9510646) (author), Rachel E. Foong (15296471) (author), Sarah E. Harris (7693751) (author), Adele Taylor (677047) (author), Paul Redmond (107693) (author), James P. Cook (7643396) (author), Anubha Mahajan (206768) (author), Lars Lind (88400) (author), Teemu Palviainen (799966) (author), Terho Lehtimäki (49739) (author), Olli T. Raitakari (7588757) (author), Jaakko Kaprio (43154) (author), Taina Rantanen (200021) (author), Kirsi H. Pietiläinen (9375132) (author), Simon R. Cox (3824575) (author), Craig E. Pennell (102109) (author), Graham L. Hall (14010894) (author), W. James Gauderman (9690328) (author), Chris Brightling (603623) (author), James F. Wilson (7638917) (author), Tuula Vasankari (82439) (author), Tarja Laitinen (131542) (author), Veikko Salomaa (62543) (author), Dennis O. Mook-Kanamori (148319) (author), Nicholas J. Timpson (7243103) (author), Eleftheria Zeggini (21702) (author), Josée Dupuis (28859) (author), Caroline Hayward (149856) (author), Ben Brumpton (6281339) (author), Claudia Langenberg (160616) (author), Stefan Weiss (1474864) (author), Georg Homuth (110202) (author), Carsten Oliver Schmidt (7359722) (author), Nicole Probst-Hensch (520032) (author), Marjo-Riitta Jarvelin (110290) (author), Alanna C. Morrison (7634126) (author), Ozren Polasek (3965693) (author), Igor Rudan (150101) (author), Joo-Hyeon Lee (9280379) (author), Ian Sayers (37266) (author), Emma L. Rawlins (12773552) (author), Frank Dudbridge (102283) (author), Edwin K. Silverman (6856082) (author), David P. Strachan (7634177) (author), Robin G. Walters (10094785) (author), Andrew P. Morris (6733298) (author), Stephanie J. London (7634180) (author), Michael H. Cho (6856079) (author), Louise V. Wain (7588511) (author), Ian P. Hall (7377620) (author), Martin D. Tobin (7581161) (author)
Published: 2023
Subjects:
Biological sciences
Genetics
Biomedical and clinical sciences
Cardiovascular medicine and haematology
Clinical sciences
Genome-wide association studies
Respiratory tract diseases
Lung-function impairment
Chronic obstructive pulmonary disease (COPD)
Genome-wide association studies (GWAS)
Multi-ancestry study
Genetic risk score (GRS)
Genetic variants
Drug development
Respiratory disease
Heritability
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Summary:<p dir="ltr">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 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.</p><p dir="ltr">Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk: <a href="https://doi.org/10.1038/s41588-023-01531-7" target="_blank">https://doi.org/10.1038/s41588-023-01531-7</a>, published online 25 September 2023.</p><h2>Other Information</h2><p dir="ltr">Published in: Nature Genetics<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41588-023-01314-0" target="_blank">https://dx.doi.org/10.1038/s41588-023-01314-0</a></p><p dir="ltr">Additional institutions affiliated with: Hamad Medical Corporation, Qatar University Health - QU, Clinical Research Centre - Sidra Medicine</p>

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