Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features. We hypothesized that polygenic risk scores (PRSs) for asthma (PRSAsthma) and spirometry (FEV1 and FEV1/FVC; PRSspiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO). We developed and tested two asthma PRSs and applied the higher performing PRSAsthma and a previously-published PRSspiro 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. In meta-analyses of 102,477 participants, the PRSAsthma (OR per SD 1.16 [95% CI: 1.14-1.19]) and PRSspiro (OR per SD 1.19 [95% CI: 1.17-1.22]) both predicted asthma, while the PRSspiro predicted COPD (OR per SD 1.25 [95% CI: 1.21-1.30]). However, results differed by cohort. The PRSspiro was not associated with COPD in GERA and MGB. In COPDGene, the PRSAsthma (OR per SD: Whites: 1.3; African Americans (AA): 1.2) and PRSspiro (OR per SD: Whites: 2.2; AA: 1.6) were both associated with ACO. In GERA, the PRSAsthma was associated with asthma exacerbations (OR 1.18) in whites; the PRSspiro was associated with asthma exacerbations in white, LatinX, and East Asian participants. 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.

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