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Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.

TitlePolygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.
Publication TypeJournal Article
Year of Publication2022
AuthorsHu X, Qiao D, Kim W, Moll M, Balte PP, Lange LA, Bartz TM, Kumar R, Li X, Yu B, Cade BE, Laurie CA, Sofer T, Ruczinski I, Nickerson DA, Muzny DM, Metcalf GA, Doddapaneni HV, Gabriel S, Gupta N, Dugan-Perez S, L Cupples A, Loehr LR, Jain D, Rotter JI, Wilson JG, Psaty BM, Fornage M, Morrison AC, Vasan RS, Washko G, Rich SS, O'Connor GT, Bleecker E, Kaplan RC, Kalhan R, Redline S, Gharib SA, Meyers D, Ortega V, Dupuis J, London SJ, Lappalainen T, Oelsner EC, Silverman EK, Barr GR, Thornton TA, Wheeler HE, Cho MH, Im HKyung, Manichaikul A
Corporate AuthorsTOPMed Lung Working Group
JournalAm J Hum Genet
Date Published2022 05 05
KeywordsHumans, Lung, National Heart, Lung, and Blood Institute (U.S.), Pulmonary Disease, Chronic Obstructive, Risk Factors, Transcriptome, United States

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 [FEV] and its ratio to forced vital capacity [FEV/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 (FEV and FEV/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 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.

Alternate JournalAm J Hum Genet
PubMed ID35385699
PubMed Central IDPMC9118106
Grant ListR01 HL105756 / HL / NHLBI NIH HHS / United States
R15 HG009569 / HG / NHGRI NIH HHS / United States
R03 HL154284 / HL / NHLBI NIH HHS / United States
R01 HL131565 / HL / NHLBI NIH HHS / United States
R01 HL153248 / HL / NHLBI NIH HHS / United States
R01 HL153805 / HL / NHLBI NIH HHS / United States