Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

Catherine John, María Soler Artigas, Jennie Hui, Sune Fallgaard Nielsen, Nicholas Rafaels, Peter D. Paré, Nadia Hansel, Nick Shrine, Iain Kilty, Anders Malarstig, Scott A. Jelinsky, Signe Vedel-Krogh, Kathleen Barnes, Ian P. Hall, John Beilby, Arthur W. Musk, Børge G. Nordestgaard, Alan James, Louise V. Wain, Martin D. Tobin

Research output: Contribution to journalArticle

Abstract

Background Genome-wide association studies have identified numerous genetic regions that influence crosssectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined. Objectives We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline. Methods We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts. Results The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts. Conclusions Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

Original languageEnglish (US)
Pages (from-to)400-408
Number of pages9
JournalThorax
Volume72
Issue number5
DOIs
StatePublished - 2017

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Lung
Genome
Genome-Wide Association Study
Spirometry
Chronic Obstructive Pulmonary Disease
Cohort Studies
Health

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

John, C., Artigas, M. S., Hui, J., Nielsen, S. F., Rafaels, N., Paré, P. D., ... Tobin, M. D. (2017). Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline. Thorax, 72(5), 400-408. https://doi.org/10.1136/thoraxjnl-2016-208448

Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline. / John, Catherine; Artigas, María Soler; Hui, Jennie; Nielsen, Sune Fallgaard; Rafaels, Nicholas; Paré, Peter D.; Hansel, Nadia; Shrine, Nick; Kilty, Iain; Malarstig, Anders; Jelinsky, Scott A.; Vedel-Krogh, Signe; Barnes, Kathleen; Hall, Ian P.; Beilby, John; Musk, Arthur W.; Nordestgaard, Børge G.; James, Alan; Wain, Louise V.; Tobin, Martin D.

In: Thorax, Vol. 72, No. 5, 2017, p. 400-408.

Research output: Contribution to journalArticle

John, C, Artigas, MS, Hui, J, Nielsen, SF, Rafaels, N, Paré, PD, Hansel, N, Shrine, N, Kilty, I, Malarstig, A, Jelinsky, SA, Vedel-Krogh, S, Barnes, K, Hall, IP, Beilby, J, Musk, AW, Nordestgaard, BG, James, A, Wain, LV & Tobin, MD 2017, 'Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline', Thorax, vol. 72, no. 5, pp. 400-408. https://doi.org/10.1136/thoraxjnl-2016-208448
John, Catherine ; Artigas, María Soler ; Hui, Jennie ; Nielsen, Sune Fallgaard ; Rafaels, Nicholas ; Paré, Peter D. ; Hansel, Nadia ; Shrine, Nick ; Kilty, Iain ; Malarstig, Anders ; Jelinsky, Scott A. ; Vedel-Krogh, Signe ; Barnes, Kathleen ; Hall, Ian P. ; Beilby, John ; Musk, Arthur W. ; Nordestgaard, Børge G. ; James, Alan ; Wain, Louise V. ; Tobin, Martin D. / Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline. In: Thorax. 2017 ; Vol. 72, No. 5. pp. 400-408.
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title = "Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline",
abstract = "Background Genome-wide association studies have identified numerous genetic regions that influence crosssectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined. Objectives We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline. Methods We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts. Results The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts. Conclusions Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.",
author = "Catherine John and Artigas, {Mar{\'i}a Soler} and Jennie Hui and Nielsen, {Sune Fallgaard} and Nicholas Rafaels and Par{\'e}, {Peter D.} and Nadia Hansel and Nick Shrine and Iain Kilty and Anders Malarstig and Jelinsky, {Scott A.} and Signe Vedel-Krogh and Kathleen Barnes and Hall, {Ian P.} and John Beilby and Musk, {Arthur W.} and Nordestgaard, {B{\o}rge G.} and Alan James and Wain, {Louise V.} and Tobin, {Martin D.}",
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T1 - Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

AU - John, Catherine

AU - Artigas, María Soler

AU - Hui, Jennie

AU - Nielsen, Sune Fallgaard

AU - Rafaels, Nicholas

AU - Paré, Peter D.

AU - Hansel, Nadia

AU - Shrine, Nick

AU - Kilty, Iain

AU - Malarstig, Anders

AU - Jelinsky, Scott A.

AU - Vedel-Krogh, Signe

AU - Barnes, Kathleen

AU - Hall, Ian P.

AU - Beilby, John

AU - Musk, Arthur W.

AU - Nordestgaard, Børge G.

AU - James, Alan

AU - Wain, Louise V.

AU - Tobin, Martin D.

PY - 2017

Y1 - 2017

N2 - Background Genome-wide association studies have identified numerous genetic regions that influence crosssectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined. Objectives We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline. Methods We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts. Results The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts. Conclusions Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

AB - Background Genome-wide association studies have identified numerous genetic regions that influence crosssectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined. Objectives We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline. Methods We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts. Results The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts. Conclusions Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

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