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Title: Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts
Authors: Matthew Moll
Phuwanat Sakornsakolpat
Nick Shrine
Brian D. Hobbs
Dawn L. DeMeo
Catherine John
Anna L. Guyatt
Michael J. McGeachie
Sina A. Gharib
Ma'en Obeidat
Lies Lahousse
Sara R.A. Wijnant
Guy Brusselle
Deborah A. Meyers
Eugene R. Bleecker
Xingnan Li
Ruth Tal-Singer
Ani Manichaikul
Stephen S. Rich
Sungho Won
Woo Jin Kim
Ah Ra Do
George R. Washko
R. Graham Barr
Bruce M. Psaty
Traci M. Bartz
Nadia N. Hansel
Kathleen Barnes
John E. Hokanson
James D. Crapo
David Lynch
Per Bakke
Amund Gulsvik
Ian P. Hall
Louise Wain
María Soler Artigas
Victoria E. Jackson
David P. Strachan
Jennie Hui
Alan L. James
Shona M. Kerr
Ozren Polasek
Veronique Vitart
Jonathan Marten
Igor Rudan
Mika Kähönen
Ida Surakka
Christian Gieger
Stefan Karrasch
Rajesh Rawal
Holger Schulz
Ian J. Deary
Sarah E. Harris
Stefan Enroth
Ulf Gyllensten
Medea Imboden
Nicole M. Probst-Hensch
Terho Lehtimäki
Olli T. Raitakari
Claudia Langenberg
Jian'an Luan
Nick Wareham
Jing Hua Zhao
Caroline Hayward
Alison Murray
David J. Porteous
Blair H. Smith
Marjo Riitta Jarvelin
Matthias Wielscher
Peter K. Joshi
Katherine A. Kentistou
Paul RHJ Timmers
James F. Wilson
James P. Cook
Lars Lind
Anubha Mahajan
Andrew P. Morris
Ralf Ewert
Georg Homuth
Beate Stubbe
Stefan Weiss
Eleftheria Zeggini
Scott T. Weiss
Edwin K. Silverman
Frank Dudbridge
Martin D. Tobin
Michael H. Cho
National Jewish Health
GlaxoSmithKline, USA
University Hospital of Ghent
Universiteit Gent
University of Leicester
Erasmus MC
University of Virginia School of Medicine
Queen's Medical Centre
Universitetet i Bergen
University of Washington School of Medicine
University of Colorado at Denver Anschutz Medical Campus
Columbia University Irving Medical Center
University of Virginia
Kaiser Permanente
Brigham and Women's Hospital
University of Washington, Seattle
Seoul National University
Faculty of Medicine, Siriraj Hospital, Mahidol University
The University of British Columbia
University of Colorado at Denver
The University of Arizona
Glenfield Hospital
Johns Hopkins University
Harvard Medical School
Kangwon National University
Keywords: Medicine
Issue Date: 1-Jul-2020
Citation: The Lancet Respiratory Medicine. Vol.8, No.7 (2020), 696-708
Abstract: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. Funding: US National Institutes of Health, Wellcome Trust.
ISSN: 22132619
Appears in Collections:Scopus 2020

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