Multi-trait Polygenic Scores for COPD and COPD Exacerbations Implicate Druggable Proteins

Authors

• Chengyue Zhang
• Iain R Konigsberg
• Yixuan He
• Jingzhou Zhang
• Tinashe Chikowore
• William B Feldman
• Xiaowei Hu
• Yi Ding
• Bogdan Pasaniuc
• Diana Chang
• Qingwen Chen
• Jessica A Lasky-Su
• Julian Hecker
• Martin D Tobin
• Jing Chen
• Sean Kalra
• Katherine A Pratte
• Hae Kyung Im
• Emily S Wan
• Ani Manichaikul
• Edwin K Silverman
• Russell P Bowler
• Leslie A Lange
• Victor E Ortega
• Alicia R Martin
• Michael H Cho
• Matthew R Moll

Language

English

Publication Date

4-8-2026

Journal

JCI Insight

DOI

10.1172/jci.insight.199951

PMID

41712304

PMCID

PMC13134720

PubMedCentral® Posted Date

2-19-2026

PubMedCentral® Full Text Version

Post-print

Abstract

BACKGROUND

We constructed multi-trait polygenic risk scores (PRSs) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validated their performance in diverse cohorts, and identified PRS-related proteins for potential therapeutic targeting.

METHODS

PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic White participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2–4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), Mass General Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012).

RESULTS

PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects [RE] OR 1.58 [95% CI: 1.28–1.94]) and exacerbation frequency (meta-analysis RE β 0.21 [95% CI: 0.11–0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRSs that were also validated with measured protein levels in COPDGene and UK Biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include RAGE/sRAGE, IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations.

CONCLUSIONS

Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management.

Keywords

Humans, Pulmonary Disease, Chronic Obstructive, Genetic Risk Score, Female, Male, Aged, Middle Aged, Genetic Predisposition to Disease, Disease Progression, Proteomics, Genome-Wide Association Study, Multifactorial Inheritance, Genetics, Pulmonology, COPD, Genetic risk factors, Proteomics

Comments

TRIAL REGISTRATION

COPDGene: ClinicalTrials.gov NCT00608764; ECLIPSE: ClinicalTrials.gov NCT00292552.

Published Open-Access

yes

Recommended Citation

Zhang, Chengyue; Konigsberg, Iain R; He, Yixuan; et al., "Multi-trait Polygenic Scores for COPD and COPD Exacerbations Implicate Druggable Proteins" (2026). Faculty, Staff and Student Publications. 1453.
https://digitalcommons.library.tmc.edu/uthsph_docs/1453