Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study

Natalia Hernandez-Pacheco; Anna Kilanowski; Ashish Kumar; CADSET Clinical Research Collaboration of the European Respiratory Society; John A. Curtin; Núria Olvera; Sara Kress; Xander Bertels; Lies Lahousse; Laxmi Bhatta; Raquel Granell; Sergi Marí; Jose Ramon Bilbao; Yidan Sun; Casper Emil Tingskov Pedersen; Tarik Karramass; Elisabeth Thiering; Christina Dardani; Simon Kebede Merid; Gang Wang; Jenny Hallberg; Sarah Koch; Judith Garcia-Aymerich; Ana Esplugues; Maties Torrent; Jesus Ibarluzea; Lesley Lowe; Angela Simpson; Ulrike Gehring; Roel C.H. Vermeulen; Graham Roberts; Anna Bergström; Judith M. Vonk; Janine F. Felix; Liesbeth Duijts; Klaus Bønnelykke; Nic Timpson; Guy Brusselle; Ben M. Brumpton; Arnulf Langhammer; Stephen Turner; John W. Holloway; Syed Hasan Arshad; Anhar Ullah; Adnan Custovic; Paul Cullinan; Clare S. Murray; Maarten van den Berge; Inger Kull; Tamara Schikowski; Jadwiga A. Wedzicha

doi:10.1016/j.eclinm.2024.102731

Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study

Natalia Hernandez-Pacheco^*, Anna Kilanowski, Ashish Kumar, CADSET Clinical Research Collaboration of the European Respiratory Society, John A. Curtin, Núria Olvera, Sara Kress, Xander Bertels, Lies Lahousse, Laxmi Bhatta, Raquel Granell, Sergi Marí, Jose Ramon Bilbao, Yidan Sun, Casper Emil Tingskov Pedersen, Tarik Karramass, Elisabeth Thiering, Christina Dardani, Simon Kebede Merid, Gang WangJenny Hallberg, Sarah Koch, Judith Garcia-Aymerich, Ana Esplugues, Maties Torrent, Jesus Ibarluzea, Lesley Lowe, Angela Simpson, Ulrike Gehring, Roel C.H. Vermeulen, Graham Roberts, Anna Bergström, Judith M. Vonk, Janine F. Felix, Liesbeth Duijts, Klaus Bønnelykke, Nic Timpson, Guy Brusselle, Ben M. Brumpton, Arnulf Langhammer, Stephen Turner, John W. Holloway, Syed Hasan Arshad, Anhar Ullah, Adnan Custovic, Paul Cullinan, Clare S. Murray, Maarten van den Berge, Inger Kull, Tamara Schikowski, Jadwiga A. Wedzicha

^*Corresponding author for this work

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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 (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.

Original language	English
Article number	102731
Journal	EClinicalMedicine
Volume	75
DOIs	https://doi.org/10.1016/j.eclinm.2024.102731
Publication status	Published - Sept 2024

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Hernandez-Pacheco, N., Kilanowski, A., Kumar, A., CADSET Clinical Research Collaboration of the European Respiratory Society, Curtin, J. A., Olvera, N., Kress, S., Bertels, X., Lahousse, L., Bhatta, L., Granell, R., Marí, S., Bilbao, J. R., Sun, Y., Tingskov Pedersen, C. E., Karramass, T., Thiering, E., Dardani, C., Kebede Merid, S., ... Wedzicha, J. A. (2024). Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study. EClinicalMedicine, 75, Article 102731. https://doi.org/10.1016/j.eclinm.2024.102731

@article{d8f7fd2e26ec4a96bdadddc86b8f2162,

title = "Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study",

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 (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.",

author = "Natalia Hernandez-Pacheco and Anna Kilanowski and Ashish Kumar and {CADSET Clinical Research Collaboration of the European Respiratory Society} and Curtin, {John A.} and N{\'u}ria Olvera and Sara Kress and Xander Bertels and Lies Lahousse and Laxmi Bhatta and Raquel Granell and Sergi Mar{\'i} and Bilbao, {Jose Ramon} and Yidan Sun and {Tingskov Pedersen}, {Casper Emil} and Tarik Karramass and Elisabeth Thiering and Christina Dardani and {Kebede Merid}, Simon and Gang Wang and Jenny Hallberg and Sarah Koch and Judith Garcia-Aymerich and Ana Esplugues and Maties Torrent and Jesus Ibarluzea and Lesley Lowe and Angela Simpson and Ulrike Gehring and Vermeulen, {Roel C.H.} and Graham Roberts and Anna Bergstr{\"o}m and Vonk, {Judith M.} and Felix, {Janine F.} and Liesbeth Duijts and Klaus B{\o}nnelykke and Nic Timpson and Guy Brusselle and Brumpton, {Ben M.} and Arnulf Langhammer and Stephen Turner and Holloway, {John W.} and Arshad, {Syed Hasan} and Anhar Ullah and Adnan Custovic and Paul Cullinan and Murray, {Clare S.} and {van den Berge}, Maarten and Inger Kull and Tamara Schikowski and Wedzicha, {Jadwiga A.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = sep,

doi = "10.1016/j.eclinm.2024.102731",

language = "English",

volume = "75",

journal = "EClinicalMedicine",

issn = "2589-5370",

publisher = "Elsevier Ltd.",

}

Hernandez-Pacheco, N, Kilanowski, A, Kumar, A, CADSET Clinical Research Collaboration of the European Respiratory Society, Curtin, JA, Olvera, N, Kress, S, Bertels, X , Lahousse, L, Bhatta, L, Granell, R, Marí, S, Bilbao, JR, Sun, Y, Tingskov Pedersen, CE, Karramass, T, Thiering, E, Dardani, C, Kebede Merid, S, Wang, G, Hallberg, J, Koch, S, Garcia-Aymerich, J, Esplugues, A, Torrent, M, Ibarluzea, J, Lowe, L, Simpson, A, Gehring, U, Vermeulen, RCH, Roberts, G, Bergström, A, Vonk, JM, Felix, JF , Duijts, L, Bønnelykke, K, Timpson, N, Brusselle, G, Brumpton, BM, Langhammer, A, Turner, S, Holloway, JW, Arshad, SH, Ullah, A, Custovic, A, Cullinan, P, Murray, CS, van den Berge, M, Kull, I, Schikowski, T & Wedzicha, JA 2024, 'Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study', EClinicalMedicine, vol. 75, 102731. https://doi.org/10.1016/j.eclinm.2024.102731

TY - JOUR

T1 - Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study

AU - Hernandez-Pacheco, Natalia

AU - Kilanowski, Anna

AU - Kumar, Ashish

AU - CADSET Clinical Research Collaboration of the European Respiratory Society

AU - Curtin, John A.

AU - Olvera, Núria

AU - Kress, Sara

AU - Bertels, Xander

AU - Lahousse, Lies

AU - Bhatta, Laxmi

AU - Granell, Raquel

AU - Marí, Sergi

AU - Bilbao, Jose Ramon

AU - Sun, Yidan

AU - Tingskov Pedersen, Casper Emil

AU - Karramass, Tarik

AU - Thiering, Elisabeth

AU - Dardani, Christina

AU - Kebede Merid, Simon

AU - Wang, Gang

AU - Hallberg, Jenny

AU - Koch, Sarah

AU - Garcia-Aymerich, Judith

AU - Esplugues, Ana

AU - Torrent, Maties

AU - Ibarluzea, Jesus

AU - Lowe, Lesley

AU - Simpson, Angela

AU - Gehring, Ulrike

AU - Vermeulen, Roel C.H.

AU - Roberts, Graham

AU - Bergström, Anna

AU - Vonk, Judith M.

AU - Felix, Janine F.

AU - Duijts, Liesbeth

AU - Bønnelykke, Klaus

AU - Timpson, Nic

AU - Brusselle, Guy

AU - Brumpton, Ben M.

AU - Langhammer, Arnulf

AU - Turner, Stephen

AU - Holloway, John W.

AU - Arshad, Syed Hasan

AU - Ullah, Anhar

AU - Custovic, Adnan

AU - Cullinan, Paul

AU - Murray, Clare S.

AU - van den Berge, Maarten

AU - Kull, Inger

AU - Schikowski, Tamara

AU - Wedzicha, Jadwiga A.

PY - 2024/9

Y1 - 2024/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85203075860&partnerID=8YFLogxK

U2 - 10.1016/j.eclinm.2024.102731

DO - 10.1016/j.eclinm.2024.102731

M3 - Article

AN - SCOPUS:85203075860

SN - 2589-5370

VL - 75

JO - EClinicalMedicine

JF - EClinicalMedicine

M1 - 102731

ER -

Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study

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