• 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, International COPD Genetics Consortium, SpiroMeta Consortium, Scott T Weiss, Edwin K Silverman, Frank Dudbridge, Martin D Tobin, and Michael H Cho.
• Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
• Lancet Respir Med. 2020 Jul 1; 8 (7): 696-708.

BackgroundGenetic 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.MethodsWe 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.FindingsThe 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.InterpretationA 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.FundingUS National Institutes of Health, Wellcome Trust.Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

17 keywords...

hide…