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 af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

Background
Chronic obstructive pulmonary disease may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition.
Objectives
We investigated the extent to which 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/forced vital capacity [FVC]) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the The Lundbeck Foundation Initiative for Integrative Psychiactric Research (iPSYCH) cohort.
Results
The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (eg, neonatal FEV0.5/FVC [β: −0.20; 95% CI: −0.31 to −0.09; P < .0003]), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (odds ratio: 1.24; 95% CI: 1.19-1.29; P = 1.6 × 10−26) and lower respiratory tract infections (odds ratio: 1.09; 95% CI: 1.06-1.12; P = 3.5 × 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.
Conclusions
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.

Originalsprog	Engelsk
Tidsskrift	Journal of Allergy and Clinical Immunology
Vol/bind	156
Udgave nummer	4
Sider (fra-til)	937-947
Antal sider	11
ISSN	0091-6749
DOI	https://doi.org/10.1016/j.jaci.2025.06.035
Status	Udgivet - 2025

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© 2025 The Authors

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Citationsformater

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

Pedersen, CET, Eliasen, A, Fischer-Rasmussen, K, Luo, Y, Skov, F, Sevelsted, A, Thorsen, J , Stæhr Jensen, JU, 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, bind 156, nr. 4, s. 937-947. https://doi.org/10.1016/j.jaci.2025.06.035

@article{05d068aafe8a496994da95057f530b00,

title = "Genetic risk for adult obstructive lung function and its early life associations",

abstract = "Background: Chronic obstructive pulmonary disease may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition. Objectives: We investigated the extent to which 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/forced vital capacity [FVC]) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the The Lundbeck Foundation Initiative for Integrative Psychiactric Research (iPSYCH) cohort. Results: The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (eg, neonatal FEV0.5/FVC [β: −0.20; 95% CI: −0.31 to −0.09; P < .0003]), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (odds ratio: 1.24; 95% CI: 1.19-1.29; P = 1.6 × 10−26) and lower respiratory tract infections (odds ratio: 1.09; 95% CI: 1.06-1.12; P = 3.5 × 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. Conclusions: 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 = "asthma exacerbations, chronic obstructive pulmonary disease, COPD, lung function trajectories, Neonatal lung function, polygenic risk scores, spirometry",

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",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

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 = "Mosby Inc.",

number = "4",

}

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 may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition. Objectives: We investigated the extent to which 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/forced vital capacity [FVC]) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the The Lundbeck Foundation Initiative for Integrative Psychiactric Research (iPSYCH) cohort. Results: The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (eg, neonatal FEV0.5/FVC [β: −0.20; 95% CI: −0.31 to −0.09; P < .0003]), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (odds ratio: 1.24; 95% CI: 1.19-1.29; P = 1.6 × 10−26) and lower respiratory tract infections (odds ratio: 1.09; 95% CI: 1.06-1.12; P = 3.5 × 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. Conclusions: 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 may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition. Objectives: We investigated the extent to which 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/forced vital capacity [FVC]) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the The Lundbeck Foundation Initiative for Integrative Psychiactric Research (iPSYCH) cohort. Results: The FEV1/FVC PRS was associated with obstructive lung function shortly after birth (eg, neonatal FEV0.5/FVC [β: −0.20; 95% CI: −0.31 to −0.09; P < .0003]), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (odds ratio: 1.24; 95% CI: 1.19-1.29; P = 1.6 × 10−26) and lower respiratory tract infections (odds ratio: 1.09; 95% CI: 1.06-1.12; P = 3.5 × 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. Conclusions: 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 - asthma exacerbations

KW - chronic obstructive pulmonary disease

KW - COPD

KW - lung function trajectories

KW - Neonatal lung function

KW - polygenic risk scores

KW - spirometry

U2 - 10.1016/j.jaci.2025.06.035

DO - 10.1016/j.jaci.2025.06.035

M3 - Journal article

C2 - 40706879

AN - SCOPUS:105014966496

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 -