Matthew MollPhuwanat SakornsakolpatNick ShrineBrian D. HobbsDawn L. DeMeoCatherine JohnAnna L. GuyattMichael J. McGeachieSina A. GharibMa'en ObeidatLies LahousseSara R.A. WijnantGuy BrusselleDeborah A. MeyersEugene R. BleeckerXingnan LiRuth Tal-SingerAni ManichaikulStephen S. RichSungho WonWoo Jin KimAh Ra DoGeorge R. WashkoR. Graham BarrBruce M. PsatyTraci M. BartzNadia N. HanselKathleen BarnesJohn E. HokansonJames D. CrapoDavid LynchPer BakkeAmund GulsvikIan P. HallLouise WainMaría Soler ArtigasVictoria E. JacksonDavid P. StrachanJennie HuiAlan L. JamesShona M. KerrOzren PolasekVeronique VitartJonathan MartenIgor RudanMika KähönenIda SurakkaChristian GiegerStefan KarraschRajesh RawalHolger SchulzIan J. DearySarah E. HarrisStefan EnrothUlf GyllenstenMedea ImbodenNicole M. Probst-HenschTerho LehtimäkiOlli T. RaitakariClaudia LangenbergJian'an LuanNick WarehamJing Hua ZhaoCaroline HaywardAlison MurrayDavid J. PorteousBlair H. SmithMarjo Riitta JarvelinMatthias WielscherPeter K. JoshiKatherine A. KentistouPaul RHJ TimmersJames F. WilsonJames P. CookLars LindAnubha MahajanAndrew P. MorrisRalf EwertGeorg HomuthBeate StubbeStefan WeissEleftheria ZegginiScott T. WeissEdwin K. SilvermanFrank DudbridgeMartin D. TobinMichael H. ChoNational Jewish HealthGlaxoSmithKline, USAUniversity Hospital of GhentUniversiteit GentUniversity of LeicesterErasmus MCUniversity of Virginia School of MedicineQueen's Medical CentreUniversitetet i BergenUniversity of Washington School of MedicineUniversity of Colorado at Denver Anschutz Medical CampusColumbia University Irving Medical CenterUniversity of VirginiaKaiser PermanenteBrigham and Women's HospitalUniversity of Washington, SeattleSeoul National UniversityFaculty of Medicine, Siriraj Hospital, Mahidol UniversityThe University of British ColumbiaUniversity of Colorado at DenverThe University of ArizonaGlenfield HospitalJohns Hopkins UniversityHarvard Medical SchoolKangwon National University2020-08-252020-08-252020-07-01The Lancet Respiratory Medicine. Vol.8, No.7 (2020), 696-70822132619221326002-s2.0-85087427951https://repository.li.mahidol.ac.th/handle/20.500.14594/58118© 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.Mahidol UniversityMedicineArticleSCOPUS10.1016/S2213-2600(20)30101-6