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

Abstract

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≤5x10-8) 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=7·04x10-53) to adulthood (41-50 years; β: -0·16 [-0·19, -0·13], q-value=1·31x10-24); and (2) lower FEV1 (from school age: 7-10 years; β: -0·07 [-0·09, -0·05], q-value=1.65x10-9, 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.

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Identifiers

ORCID for John Holloway: orcid.org/0000-0001-9998-0464

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