Exploring the genetics of airflow limitation in lung function across the lifespan - a polygenic risk score study

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is caused by interactions between many factors across the life course, including genetics. A proportion of COPD may be due to reduced lung growth in childhood. We hypothesized that a polygenic risk score (PRS) for COPD is associated with lower lung function already in childhood and up to adulthood. METHODS: A weighted PRS was calculated based on the 82 association signals (p ≤ 5 × 10⁻⁸) revealed by the largest GWAS of airflow limitation (defined as COPD) to date. This PRS was tested in association with lung function measures (FEV₁, FVC, and FEV₁/FVC) in subjects aged 4-50 years from 16 independent cohorts participating in the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration. Age-stratified meta-analyses were conducted combining the results from each cohort (n = 45,406). These findings were validated in subjects >50 years old. FINDINGS: We found significant associations between the PRS for airflow limitation and: (1) lower pre-bronchodilator FEV₁/FVC from school age (7-10 years; β: -0.13 z-scores per one PRS z-score increase [-0.15, -0.11], q-value = 7.04 × 10⁻⁵³) to adulthood (41-50 years; β: -0.16 [-0.19, -0.13], q-value = 1.31 × 10⁻²⁴); and (2) lower FEV₁ (from school age: 7-10 years; β: -0.07 [-0.09, -0.05], q-value = 1.65 × 10⁻⁹, to adulthood: 41-50 years; β: -0.17 [-0.20, -0.13], q-value = 4.48 x 10⁻²⁰). No effect modification by smoking, sex, or a diagnosis of asthma was observed. INTERPRETATION: We provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards. FUNDING: This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.