Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations

Casper-Emil T. Pedersen; Anders Eliasen; Kasper Fischer-Rasmussen; Yang Luo; Frederikke Skov; Astrid Sevelsted; Jonathan Thorsen; Jens-Ulrik Stæhr Jensen; Jørgen Vestbo; Thomas Werge; Andreanne Morin; Carole Ober; Morten A. Rasmussen; George Davey Smith; Jakob Stokholm; Bo Chawes; Klaus Bønnelykke

doi:10.1016/j.jaci.2025.06.035

Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations

Casper-Emil T. Pedersen
, Anders Eliasen
, Kasper Fischer-Rasmussen
, Yang Luo
, Frederikke Skov
, Astrid Sevelsted
, Jonathan Thorsen
, Jens-Ulrik Stæhr Jensen
, Jørgen Vestbo
, Thomas Werge
, Andreanne Morin
, Carole Ober
, Morten A. Rasmussen
, George Davey Smith
, Jakob Stokholm
, Bo Chawes
, Klaus Bønnelykke^*

^*Corresponding author for this work

Department of Biotechnology and Biomedicine

Copenhagen University Hospital Herlev and Gentofte
University of Manchester
Rigshospitalet
The University of Chicago
University of Bristol

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Background: Chronic obstructive pulmonary disease (COPD) may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition.
Objective: We investigated to which extent the genetic predisposition to adult obstructive lung function manifests already at birth and throughout childhood in terms of impaired lung function, bronchial responsiveness and asthma-related symptoms.
Methods: We constructed a polygenic risk score (PRS) for adult obstructive lung function (FEV1/FVC) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the IPSYCH cohort.
Results: The FEV₁/FVC PRS was associated with obstructive lung function shortly after birth (e.g., neonatal FEV_0.5/FVC (β: -0.20 [-0.31;-0.09], P < 0.0003)), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (OR 1.24 [1.19;1.29], P = 1.6 Χ 10^-26) and lower respiratory tract infections (OR 1.09 [1.06-1.12], P = 3.5 Χ 10^-8) requiring hospitalization, which was evident a few months after birth. In COPSAC₂₀₀₀, there was no evidence of asthma exacerbations mediating the association between FEV₁/FVC PRS and lung function by age 18 years.
Conclusion: Genetic predisposition to obstructive lung function was evident shortly after birth in terms of impaired neonatal lung function and increased susceptibility to severe wheeze, asthma, and lower respiratory tract infections. This indicates prenatal life and early childhood as a window of opportunity for improving lung health in adulthood.

Original language	English
Journal	Journal of Allergy and Clinical Immunology
Volume	156
Issue number	4
Pages (from-to)	937-947
ISSN	0091-6749
DOIs	https://doi.org/10.1016/j.jaci.2025.06.035
Publication status	Published - 2025

Keywords

Neonatal lung function
Lung function trajectories
hronic obstructive pulmonary disease
COPD
Spiometry
Polygenetic risk scores
Asthma exacerbations

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Pedersen, C.-E. T., Eliasen, A., Fischer-Rasmussen, K., Luo, Y., Skov, F., Sevelsted, A., Thorsen, J., Stæhr Jensen, J.-U., Vestbo, J., Werge, T., Morin, A., Ober, C., Rasmussen, M. A., Davey Smith, G., Stokholm, J., Chawes, B., & Bønnelykke, K. (2025). Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations. Journal of Allergy and Clinical Immunology, 156(4), 937-947. https://doi.org/10.1016/j.jaci.2025.06.035

@article{71d1789f78354822ac18a5ce33ca2adc,

title = "Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations",

abstract = "Background: Chronic obstructive pulmonary disease (COPD) may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition. Objective: We investigated to which extent the genetic predisposition to adult obstructive lung function manifests already at birth and throughout childhood in terms of impaired lung function, bronchial responsiveness and asthma-related symptoms. Methods: We constructed a polygenic risk score (PRS) for adult obstructive lung function (FEV1/FVC) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the IPSYCH cohort. Results: The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (e.g., neonatal FEV0.5/FVC (β: -0.20 [-0.31;-0.09], P < 0.0003)), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (OR 1.24 [1.19;1.29], P = 1.6 Χ 10-26) and lower respiratory tract infections (OR 1.09 [1.06-1.12], P = 3.5 Χ 10-8) requiring hospitalization, which was evident a few months after birth. In COPSAC2000, there was no evidence of asthma exacerbations mediating the association between FEV1/FVC PRS and lung function by age 18 years. Conclusion: Genetic predisposition to obstructive lung function was evident shortly after birth in terms of impaired neonatal lung function and increased susceptibility to severe wheeze, asthma, and lower respiratory tract infections. This indicates prenatal life and early childhood as a window of opportunity for improving lung health in adulthood.",

keywords = "Neonatal lung function, Lung function trajectories, hronic obstructive pulmonary disease, COPD, Spiometry, Polygenetic risk scores, Asthma exacerbations",

author = "Pedersen, \{Casper-Emil T.\} and Anders Eliasen and Kasper Fischer-Rasmussen and Yang Luo and Frederikke Skov and Astrid Sevelsted and Jonathan Thorsen and \{St{\ae}hr Jensen\}, Jens-Ulrik and J{\o}rgen Vestbo and Thomas Werge and Andreanne Morin and Carole Ober and Rasmussen, \{Morten A.\} and \{Davey Smith\}, George and Jakob Stokholm and Bo Chawes and Klaus B{\o}nnelykke",

year = "2025",

doi = "10.1016/j.jaci.2025.06.035",

language = "English",

volume = "156",

pages = "937--947",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier",

number = "4",

}

Pedersen, C-ET, Eliasen, A, Fischer-Rasmussen, K, Luo, Y, Skov, F, Sevelsted, A, Thorsen, J, Stæhr Jensen, J-U, Vestbo, J, Werge, T, Morin, A, Ober, C, Rasmussen, MA, Davey Smith, G, Stokholm, J, Chawes, B & Bønnelykke, K 2025, 'Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations', Journal of Allergy and Clinical Immunology, vol. 156, no. 4, pp. 937-947. https://doi.org/10.1016/j.jaci.2025.06.035

TY - JOUR

T1 - Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations

AU - Pedersen, Casper-Emil T.

AU - Eliasen, Anders

AU - Fischer-Rasmussen, Kasper

AU - Luo, Yang

AU - Skov, Frederikke

AU - Sevelsted, Astrid

AU - Thorsen, Jonathan

AU - Stæhr Jensen, Jens-Ulrik

AU - Vestbo, Jørgen

AU - Werge, Thomas

AU - Morin, Andreanne

AU - Ober, Carole

AU - Rasmussen, Morten A.

AU - Davey Smith, George

AU - Stokholm, Jakob

AU - Chawes, Bo

AU - Bønnelykke, Klaus

PY - 2025

Y1 - 2025

N2 - Background: Chronic obstructive pulmonary disease (COPD) may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition. Objective: We investigated to which extent the genetic predisposition to adult obstructive lung function manifests already at birth and throughout childhood in terms of impaired lung function, bronchial responsiveness and asthma-related symptoms. Methods: We constructed a polygenic risk score (PRS) for adult obstructive lung function (FEV1/FVC) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the IPSYCH cohort. Results: The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (e.g., neonatal FEV0.5/FVC (β: -0.20 [-0.31;-0.09], P < 0.0003)), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (OR 1.24 [1.19;1.29], P = 1.6 Χ 10-26) and lower respiratory tract infections (OR 1.09 [1.06-1.12], P = 3.5 Χ 10-8) requiring hospitalization, which was evident a few months after birth. In COPSAC2000, there was no evidence of asthma exacerbations mediating the association between FEV1/FVC PRS and lung function by age 18 years. Conclusion: Genetic predisposition to obstructive lung function was evident shortly after birth in terms of impaired neonatal lung function and increased susceptibility to severe wheeze, asthma, and lower respiratory tract infections. This indicates prenatal life and early childhood as a window of opportunity for improving lung health in adulthood.

AB - Background: Chronic obstructive pulmonary disease (COPD) may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition. Objective: We investigated to which extent the genetic predisposition to adult obstructive lung function manifests already at birth and throughout childhood in terms of impaired lung function, bronchial responsiveness and asthma-related symptoms. Methods: We constructed a polygenic risk score (PRS) for adult obstructive lung function (FEV1/FVC) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the IPSYCH cohort. Results: The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (e.g., neonatal FEV0.5/FVC (β: -0.20 [-0.31;-0.09], P < 0.0003)), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (OR 1.24 [1.19;1.29], P = 1.6 Χ 10-26) and lower respiratory tract infections (OR 1.09 [1.06-1.12], P = 3.5 Χ 10-8) requiring hospitalization, which was evident a few months after birth. In COPSAC2000, there was no evidence of asthma exacerbations mediating the association between FEV1/FVC PRS and lung function by age 18 years. Conclusion: Genetic predisposition to obstructive lung function was evident shortly after birth in terms of impaired neonatal lung function and increased susceptibility to severe wheeze, asthma, and lower respiratory tract infections. This indicates prenatal life and early childhood as a window of opportunity for improving lung health in adulthood.

KW - Neonatal lung function

KW - Lung function trajectories

KW - hronic obstructive pulmonary disease

KW - COPD

KW - Spiometry

KW - Polygenetic risk scores

KW - Asthma exacerbations

U2 - 10.1016/j.jaci.2025.06.035

DO - 10.1016/j.jaci.2025.06.035

M3 - Journal article

C2 - 40706879

SN - 0091-6749

VL - 156

SP - 937

EP - 947

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 4

ER -

Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations

Abstract

Keywords

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