Causal effects of early-life traits on lung function trajectory: a Mendelian randomization study
- 1University of Bristol
Abstract
Rationale At least half of chronic obstructive pulmonary disease (COPD) occurs in individuals with subnormal preceding lung function trajectory. Identifying which early-life phenotypes causally influence risk of adverse trajectories could facilitate disease prevention. Objectives Using Mendelian randomization (MR), we investigated whether previous early-life phenotypic associations with lower trajectories are compatible with a causal effect. Methods Outcomes were lower FEV1 trajectory groups from latent profile analysis in participants with [≥]2 measurements at ages 8, 15, 24 or 30 in the Avon Longitudinal Study of Parents and Children (% predicted; n=5,165). Nine exposures were prioritized for MR from observational associations with lower trajectories in logistic regression. Two-stage residual inclusion MR, applying polygenic risk scores of variants from the largest published genome-wide association studies, estimated genetically instrumented effects of exposures on odds of lower trajectories. Results Of five trajectories identified, two had lower mean FEV1: Below Average (87.7% predicted) and Persistently Low (72.6% predicted). Observationally, higher birth weight and childhood body mass index (BMI) were associated with lower odds of these trajectories, and pre-school wheeze, childhood aeroallergen sensitization, asthma and airways hyperresponsiveness with higher odds. MR evidence suggested childhood-onset asthma causally increased odds of lower trajectories (OR 9.62; 95% CI 1.49-119.7). MR estimates were directionally concordant with observational analyses but with confidence intervals crossing null for birth weight and aeroallergen sensitization, and were near-null for BMI. Conclusions These findings support a causal role for childhood-onset asthma in subnormal lung function trajectories, suggesting its optimized diagnosis and management as targets for COPD prevention.
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BibTeX
@misc{grenville2026causal,
title = {{Causal effects of early-life traits on lung function trajectory: a Mendelian randomization study}},
author = {J. S. Grenville and R. C. Richmond and G. M. Power and P. D. Yousefi and J. W. Dodd},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.26366597},
url = {https://www.medrxiv.org/content/10.64898/2026.10.27.26366597v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Causal effects of early-life traits on lung function trajectory: a Mendelian randomization study
AU - J. S. Grenville
AU - R. C. Richmond
AU - G. M. Power
AU - P. D. Yousefi
AU - J. W. Dodd
PY - 2026
DA - 2026/10/27
PB - medRxiv
DO - 10.64898/2026.10.27.26366597
UR - https://www.medrxiv.org/content/10.64898/2026.10.27.26366597v1
AB - Rationale At least half of chronic obstructive pulmonary disease (COPD) occurs in individuals with subnormal preceding lung function trajectory. Identifying which early-life phenotypes causally influence risk of adverse trajectories could facilitate disease prevention. Objectives Using Mendelian randomization (MR), we investigated whether previous early-life phenotypic associations with lower trajectories are compatible with a causal effect. Methods Outcomes were lower FEV1 trajectory groups from latent profile analysis in participants with [≥]2 measurements at ages 8, 15, 24 or 30 in the Avon Longitudinal Study of Parents and Children (% predicted; n=5,165). Nine exposures were prioritized for MR from observational associations with lower trajectories in logistic regression. Two-stage residual inclusion MR, applying polygenic risk scores of variants from the largest published genome-wide association studies, estimated genetically instrumented effects of exposures on odds of lower trajectories. Results Of five trajectories identified, two had lower mean FEV1: Below Average (87.7% predicted) and Persistently Low (72.6% predicted). Observationally, higher birth weight and childhood body mass index (BMI) were associated with lower odds of these trajectories, and pre-school wheeze, childhood aeroallergen sensitization, asthma and airways hyperresponsiveness with higher odds. MR evidence suggested childhood-onset asthma causally increased odds of lower trajectories (OR 9.62; 95% CI 1.49-119.7). MR estimates were directionally concordant with observational analyses but with confidence intervals crossing null for birth weight and aeroallergen sensitization, and were near-null for BMI. Conclusions These findings support a causal role for childhood-onset asthma in subnormal lung function trajectories, suggesting its optimized diagnosis and management as targets for COPD prevention.
ER -