Polygenic Risk Scores Identify Heterogeneity in Asthma and Chronic Obstructive Pulmonary Disease

Background: Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features.

Objective: We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRS) and spirometry (FEV and FEV/forced vital capacity; PRS) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO).

Methods: We developed and tested 2 asthma PRSs and applied the higher performing PRS and a previously published PRS to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry.

Results: In meta-analyses of 102,477 participants, the PRS (odds ratio [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, whereas 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 Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRS (OR per SD: Whites, 1.3; African Americans, 1.2) and PRS (OR per SD: Whites, 2.2; African Americans, 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: PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts.