Matthew MollSharon M. LutzAuyon J. GhoshPhuwanat SakornsakolpatCraig P. HershTerri H. BeatyFrank DudbridgeMartin D. TobinMurray A. MittlemanEdwin K. SilvermanBrian D. HobbsMichael H. ChoUniversity of LeicesterHarvard T.H. Chan School of Public HealthBeth Israel Deaconess Medical CenterBrigham and Women's HospitalHarvard Pilgrim Health CareFaculty of Medicine, Siriraj Hospital, Mahidol UniversityGlenfield HospitalJohns Hopkins Bloomberg School of Public HealthHarvard Medical School2020-12-282020-12-282020-11-25BMJ Open Respiratory Research. Vol.7, No.1 (2020)205244392-s2.0-85096817367https://repository.li.mahidol.ac.th/handle/20.500.14594/60550© 2020 Author(s). Published by BMJ. Introduction Family history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown. Methods We assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses. Results In COPDGene, family history and PRS were significantly associated with COPD in a single model (P FamHx <0.0001; P PRS <0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs. Conclusion Family history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.Mahidol UniversityMedicineArticleSCOPUS10.1136/bmjresp-2020-000755