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 N 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

doi:10.1136/thoraxjnl-2016-208448

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 N 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

Department of Clinical Medicine

16 Citations (Scopus)

64 Downloads (Pure)

Abstract

BACKGROUND: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional 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 language	English
Journal	Thorax
Volume	72
Issue number	5
Pages (from-to)	400-408
Number of pages	9
ISSN	0040-6376
DOIs	https://doi.org/10.1136/thoraxjnl-2016-208448
Publication status	Published - May 2017

Keywords

Adult
Cross-Sectional Studies
Disease Progression
Female
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Longitudinal Studies
Male
Middle Aged
Pulmonary Disease, Chronic Obstructive
Respiration
Respiratory Function Tests
Risk Assessment
Risk Factors
Spirometry
Time Factors
Western Australia
Journal Article

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Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function declineFinal published version, 999 KBLicence: CC BY

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John, C., Soler Artigas, M., Hui, J., Nielsen, S. F., Rafaels, N., Paré, P. D., Hansel, N. N., Shrine, N., Kilty, I., Malarstig, A., Jelinsky, S. A., Vedel-Krogh, S., Barnes, K., Hall, I. P., Beilby, J., Musk, A. W., Nordestgaard, B. G., James, A., Wain, L. V., & 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

John, C, Soler Artigas, M, Hui, J, Nielsen, SF, Rafaels, N, Paré, PD, Hansel, NN, 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

@article{b8dc5ba891694f71a637d728263478a8,

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 cross-sectional 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.",

keywords = "Adult, Cross-Sectional Studies, Disease Progression, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Respiration, Respiratory Function Tests, Risk Assessment, Risk Factors, Spirometry, Time Factors, Western Australia, Journal Article",

author = "Catherine John and {Soler Artigas}, Mar{\'i}a and Jennie Hui and Nielsen, {Sune Fallgaard} and Nicholas Rafaels and Par{\'e}, {Peter D} and Hansel, {Nadia N} 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}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.",

year = "2017",

month = may,

doi = "10.1136/thoraxjnl-2016-208448",

language = "English",

volume = "72",

pages = "400--408",

journal = "Thorax",

issn = "0040-6376",

publisher = "B M J Group",

number = "5",

}

TY - JOUR

T1 - Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

AU - John, Catherine

AU - Soler Artigas, María

AU - Hui, Jennie

AU - Nielsen, Sune Fallgaard

AU - Rafaels, Nicholas

AU - Paré, Peter D

AU - Hansel, Nadia N

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

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2017/5

Y1 - 2017/5

N2 - BACKGROUND: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional 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 cross-sectional 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.

KW - Adult

KW - Cross-Sectional Studies

KW - Disease Progression

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Longitudinal Studies

KW - Male

KW - Middle Aged

KW - Pulmonary Disease, Chronic Obstructive

KW - Respiration

KW - Respiratory Function Tests

KW - Risk Assessment

KW - Risk Factors

KW - Spirometry

KW - Time Factors

KW - Western Australia

KW - Journal Article

U2 - 10.1136/thoraxjnl-2016-208448

DO - 10.1136/thoraxjnl-2016-208448

M3 - Journal article

C2 - 28174340

SN - 0040-6376

VL - 72

SP - 400

EP - 408

JO - Thorax

JF - Thorax

IS - 5

ER -

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

Abstract

Keywords

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