University of Leicester
Browse
PIIS2213260020301016.pdf (481 kB)

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

Download (481 kB)
journal contribution
posted on 2020-03-24, 09:29 authored by Matthew Moll, Phuwanat Sakornsakolpat, Nicholas Shrine, Brian Hobbs, Dawn L. DeMeo, Catherine John, Anna Guyatt, 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, Wook-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 Tobin, Michael Cho
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.

History

Citation

The Lancet Respiratory Medicine, 8 (7), pp. 696-708, July 01, 2020

Author affiliation

Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

The Lancet Respiratory Medicine

Volume

8

Issue

7

Pagination

696-708

Publisher

Elsevier

issn

2213-2600

Acceptance date

2020-02-17

Copyright date

2020

Available date

2020-07-01

Language

en

Publisher version

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30101-6/fulltext

Usage metrics

    University of Leicester Publications

    Categories

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC