Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Disease areas:

• lungs

Last updated:

2 July 2025

Author(s):

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, 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, 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

Publish date:

1 July 2020

Journal:

The Lancet Respiratory Medicine

PubMed ID:

32649918

DOI:

10.1016/s2213-2600(20)30101-6

Abstract

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.