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 sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRS_Asthma) and spirometry (FEV₁ and FEV₁/forced vital capacity; PRS_spiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO).

We developed and tested 2 asthma PRSs and applied the higher performing PRS_Asthma and a previously published PRS_spiro 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.

In meta-analyses of 102,477 participants, the PRS_Asthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRS_spiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRS_spiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRS_spiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRS_Asthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRS_spiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRS_Asthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRS_spiro was associated with asthma exacerbations in White, LatinX, and East Asian participants.

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.