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

John, Catherine and Soler Artigas, María and Hui, Jennie and Nielsen, Sune Fallgaard and Rafaels, Nicholas and Paré, Peter D and Hansel, Nadia N. and Shrine, Nick and Kilty, Iain and Malarstig, Anders and Jelinsky, Scott A and Vedel-Krogh, Signe and Barnes, Kathleen and Hall, Ian P. and Beilby, John and Musk, Arthur W. and Nordestgaard, Børge G. and James, Alan and Wain, Louise V. and Tobin, Martin D. (2017) Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline. Thorax, 72 (5). pp. 400-408. ISSN 1468-3296

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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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
Identification Number: 10.1136/thoraxjnl-2016-208448
Depositing User: Eprints, Support
Date Deposited: 20 Jul 2017 15:04
Last Modified: 12 Oct 2017 23:34
URI: http://eprints.nottingham.ac.uk/id/eprint/44321

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