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.

is characterized by airway obstruction and accelerated lung function decline. However, our
understanding of systemic markers of COPD remains incomplete. Objectives: We tested whether
aptamer-based protein profiling could identify markers and pathways associated with impaired
pulmonary function and lung function decline in multiple studies. Methods: We studied 3,827
non-Hispanic and European White participants across four population-based cohorts and two
longitudinal COPD case-control studies with both aptamer-based plasma proteomic data on
1,305 proteins and spirometry measurements. In linear regression models we examined protein
associations with baseline FEV1 (Liters) and FEV1/FVC (ratio). Models for FEV1 adjusted for
age, age2, height, height 2, sex, body mass index (BMI), smoking status, pack-years smoking.
Models for FEV1/FVC ratio were adjusted for age, sex, BMI, smoking status, pack-years, and
COPD case status in COPDGene and SPIROMICS (defined as FEV1/FVC < 0.7). In linear mixed
effects models we investigated the association of baseline protein levels with rate of lung
function decline (FEV1 ml/year) in 2,636 participants across four cohorts. The model included a
random intercept and fixed effects for time, protein and its interaction with time, baseline age,
gender, height, baseline smoking status and pack-years. Benjamini-Hotchberg adjusted false
discovery rate Q-value<0.05 was used to determine statistical significance. Measurements and
Main Results: We identified 198 proteins associated with baseline FEV1, among which 12
proteins were also significantly associated with FEV1/FVC. Novel associations include retinal
binding protein 4 (FEV1: β= 0.0307; Q=2.18×10-4 and FEV1/FVC: β= 0.008; Q=4.00×10-3) and
bactericidal permeability increasing protein (FEV1: β=-0.0280; Q=6.80×10-3 and FEV1/FVC: β=-
0.005; Q=0.047). We identified 15 proteins associated with the rate of FEV1 decline (Q< 0.05),
many of which were novel including tissue factor, the coagulation cascade initiator (β= -5.21
ml/year; 95% CI, -7.82 to -2.61; Q= 0.016), nidogen, an extracellular matrix protein (β=-4.90
ml/year; 95% CI,-7.45 to -2.36; Q=0.020) and angiogenin, a potent angiogenic factor (β=-6.42;
95% CI, -9.71 to -3.14; Q=2.18×10-4). Pathways associated with lung function included
extracellular matrix remodeling, dysregulation of coagulation and angiogenesis. Conclusions: In
this study, we have identified many novel circulating protein associations with baseline lung
function and FEV1 decline. These associations could represent novel molecular targets and
pathways to modify the clinical course of COPD or be used for preventive and therapeutic
strategies.
This abstract is funded by: COPDGene Phase 3. U01 HL089897 and U01 HL089856. COPD
Foundation (AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis,
Sunovion). FHS: R01HL132320 and R01HL133870, NO1-HC-25195, HHSN268201500001I
and 75N92019D00031. KORA: German Federal Ministry of Education and Research , State of
Bavaria. LMUinnovativ, German Center for Lung Research. LSC: State of New Mexico. MESATOPMed/
MESA Lung Study: 3R01HL-120393-02S1; HHSN268201800001I.
HHSN2682015000031/HHSN26800004). R01-HL077612 and R01-HL093081. SPIROMICS:
HHSN268200900013C, HHSN268200900014C, HHSN268200900015C,
HHSN268200900016C, HHSN268200900017C, HHSN268200900018C,
HHSN268200900019C, HHSN268200900020C, U01 HL137880 and U24 HL141762,
Foundation for the NIH and COPD Foundation (AstraZeneca; Bayer, Bellerophon, Boehringer-
Ingelheim, Chiesi Farmaceutici, Forest Research, GlaxoSmithKline, Grifols, Ikaria, Novartis,
Nycomed GmbH, ProterixBio, Regeneron, Sanofi, Sunovion, Takeda, Theravance Biopharma,
Mylan).