Background: Chronic Obstructive Pulmonary Disease (COPD), diagnosed by reduced lung function, is a highly heterogeneous disease. Existing polygenic risk scores (PRS) enable early identification of genetic risk for COPD. However, predictive performance of the PRS is limited when the discovery and target populations are not well matched.
Methods: To improve cross-ethnic portability of risk prediction, we introduced a PrediXcan-derived polygenic transcriptome risk scores (PTRS), developed under the hypothesis that the biological mechanisms of disease are shared across ancestry groups. We constructed the PTRS using summary statistics from application of PrediXcan on large scale GWAS of lung function (Forced Expiratory Volume in 1 second (FEV1) and its ratio to Forced Vital Capacity (FEV1/FVC)) from the UK Biobank, which representing primarily European ancestry-based cohort. To examine prediction performance and cross-ethnic portability of the proposed PTRS candidates, we performed smoking-stratified analyses on multi-ethnic training data for 29,381 participants from TOPMed population/family-based cohorts (NHW=14,727, AA=7,025, HIS=7,629). The best risk score candidates were then tested for 11,771 multi-ethnic participants from TOPMed COPD-enriched studies (NHW=8,144, AA=3,627). Analyses were carried out for two dichotomous traits of COPD (Moderate-to-Severe and Severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC).
Results: While the novel PTRS had lower prediction accuracy for European ancestry participants than PRS, the PTRS performed slightly better than PRS for predicting COPD in heavy smoking African Americans (OR=1.24 [95%CI: 1.08-1.43] from PTRS and OR=1.10 [95% CI: 0.96-1.26] from PRS for Moderate-to-Severe COPD; for Severe COPD, OR=1.51 [95%CI: 1.04-12.19] from PTRS and OR=1.31 [95% CI: 0.87-1.96] from PRS). In addition, as hypothesized, the cross-ethnic portability was significantly higher for PTRS than for PRS (p<2.2e-16) for both dichotomous COPD traits and across all smoking strata.
Conclusions: Our study demonstrates the value of PTRS for improved prediction of COPD risk in African Americans. Future work will strengthen the PTRS framework by leveraging multi-ethnic gene expression reference data of larger sample sizes and from disease relevant tissues.