Exploring the genetics of airflow limitation in lung function across the lifespan - a polygenic risk score study
Natalia Hernandez-Pacheco1, Anna Kilanowski2,3, Ashish Kumar1
1Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Sjukhusbacken 10, 118 83, Stockholm, Sweden.
Insights
A higher genetic risk for chronic obstructive pulmonary disease (COPD) is associated with reduced lung function from childhood through adulthood. This genetic predisposition impacts lung development and function early in life.
Area of Science:
- Genetics and Respiratory Medicine
- Pulmonary Function Testing
- Epidemiology of Airway Diseases
Background:
- Chronic obstructive pulmonary disease (COPD) arises from complex interactions including genetic factors and potentially reduced lung growth in childhood.
- Genetic predisposition may influence lung development and function from an early age.
- Investigating the role of polygenic risk scores (PRS) can elucidate genetic contributions to COPD development.
Purpose of the Study:
- To investigate the association between a polygenic risk score (PRS) for COPD and lung function measures in individuals from childhood to adulthood.
- To determine if genetic risk for COPD is detectable through lung function deficits early in life.
- To validate findings across multiple independent cohorts.
Main Methods:
- A weighted polygenic risk score (PRS) was calculated using 82 genome-wide association study (GWAS) signals for airflow limitation (COPD).
- Lung function parameters (FEV1, FVC, FEV1/FVC) were assessed in 45,406 individuals aged 4-50 years across 16 cohorts.
- Age-stratified meta-analyses were performed, with validation in individuals over 50 years old.
Main Results:
- Significant associations were found between the COPD PRS and lower pre-bronchodilator FEV1/FVC from school age (7-10 years) to adulthood (41-50 years).
- Lower FEV1 was also significantly associated with the COPD PRS across the same age ranges.
- No effect modification by smoking, sex, or asthma diagnosis was observed.
Conclusions:
- This study provides evidence linking a higher genetic risk for COPD with diminished lung function starting in childhood.
- Genetic factors contribute to reduced lung function early in life, persisting into adulthood.
- The findings highlight the importance of early-life genetic influences on respiratory health and COPD risk.
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.
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