RATIONALE
Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features.
OBJECTIVES
We hypothesized that polygenic risk scores (PRSs) for asthma (PRS) and spirometry (FEV and FEV/FVC; PRS) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO).
METHODS
We developed and tested two asthma PRSs and applied the higher performing PRS and a previously-published PRS to research (COPDGene and CAMP, with spirometry) and electronic-health record (EHR)-based (MGB Biobank and GERA) studies. We assessed the association of PRSs with COPD and asthma using modified random and binary effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry.
MEASUREMENTS AND MAIN RESULTS
In meta-analyses of 102,477 participants, the PRS (OR per SD 1.16 [95% CI: 1.14-1.19]) and PRS (OR per SD 1.19 [95% CI: 1.17-1.22]) both predicted asthma, while the PRS predicted COPD (OR per SD 1.25 [95% CI: 1.21-1.30]). However, results differed by cohort. The PRS was not associated with COPD in GERA and MGB. In COPDGene, the PRS (OR per SD: Whites: 1.3; African Americans (AA): 1.2) and PRS (OR per SD: Whites: 2.2; AA: 1.6) were both associated with ACO. In GERA, the PRS was associated with asthma exacerbations (OR 1.18) in whites; the PRS was associated with asthma exacerbations in white, LatinX, and East Asian participants.
CONCLUSIONS
Polygenic risk scores for asthma and spirometry are both associated with asthma-COPD overlap and asthma exacerbations. Genetic prediction performance differs in research versus EHR-based cohorts.