Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study
Natalia Hernandez‐Pacheco, Anna Kilanowski, Ashish Kumar, John A. Curtin, Núria Olvera, Sara Kress, Xander Bertels, Lies Lahousse, Laxmi Bhatta, Raquel Granell, Sergi Marí, José Ramón Bilbao, Yidan Sun, Casper‐Emil Tingskov Pedersen, Tarik Karramass, Elisabeth Thiering, Christina Dardani, Simon Kebede Merid, Gang Wang, Jenny Hallberg, Sarah Koch, Judith García‐Aymerich, Ana Esplugues, Maties Torrent, Jesús Ibarluzea, Lesley Lowe, Angela Simpson, Ulrike Gehring, Roel Vermeulen, Graham Roberts, Anna Bergström, Judith M. Vonk, Janine F. Felix, Liesbeth Duijts, Klaus Bønnelykke, Nicholas J. Timpson, Guy Brusselle, Ben Brumpton, Arnulf Langhammer, Steve Turner, John W. Holloway, Syed Hasan Arshad, Anhar Ullah, Adnan Čustović, Paul Cullinan, Clare Murray, Maarten van den Berge, Inger Kull, Tamara Schikowski, Jadwiga A. Wedzicha, Gerard H. Koppelman, Rosa Faner, Àlvar Agustí, Marie Standl, Erik Melén
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 ≤ 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 (FEV 1 , FVC, and FEV 1 /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 FEV 1 /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 FEV 1 (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.