Faculty, Staff and Student Publications
Publication Date
5-5-2022
Journal
American Journal of Human Genetics
Abstract
While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10-16 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.
Keywords
Humans, Lung, National Heart, Lung, and Blood Institute (U.S.), Pulmonary Disease, Chronic Obstructive, Risk Factors, Transcriptome, United States, polygenic transcriptome risk score, risk prediction, cross-ethnic portability, integrative analysis, gene expression, pulmonary disease
DOI
10.1016/j.ajhg.2022.03.007
PMID
35385699
PMCID
PMC9118106
PubMedCentral® Posted Date
4-5-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Graphical Abstract
Included in
Diseases Commons, Genetic Phenomena Commons, Medical Genetics Commons, Public Health Commons