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



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.



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 FEV1and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts.



The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16for 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.



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.
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
Catherine
0000-0002-6057-2073
C
John
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
María
M
Soler Artigas
School of Pathology and Laboratory Medicine, The University of Western Australia, Australia.|PathWest, Department of Health, Government of Western Australia, Perth, WA, Australia.|Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Western Australia, Australia.|School of Population Health, The University of Western Australia, Australia.
Jennie
J
Hui
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.
Sune Fallgaard
SF
Nielsen
Center for Personalized Medicine and Biomedical Informatics, School of Medicine, University of Colorado, Anschutz Medical Campus.
Nicholas
N
Rafaels
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
Peter D
PD
Paré
Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Nadia N
NN
Hansel
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
Nick
N
Shrine
Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
Iain
I
Kilty
Pfizer Worldwide Research and Development, Stockholm, Sweden.
Anders
A
Malarstig
Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
Scott A
SA
Jelinsky
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.
Signe
S
Vedel-Krogh
Center for Personalized Medicine and Biomedical Informatics, School of Medicine, University of Colorado, Anschutz Medical Campus.
Kathleen
K
Barnes
Division of Respiratory Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Ian P
IP
Hall
School of Pathology and Laboratory Medicine, The University of Western Australia, Australia.|PathWest, Department of Health, Government of Western Australia, Perth, WA, Australia.|Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Western Australia, Australia.
John
J
Beilby
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Western Australia, Australia.|School of Population Health, The University of Western Australia, Australia.|Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.|School of Medicine and Pharmacology, The University of Western Australia, Australia.
Arthur W
AW
Musk
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.
Børge G
BG
Nordestgaard
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Western Australia, Australia.|School of Medicine and Pharmacology, The University of Western Australia, Australia.|Department of Pulmonary Physiology and Sleep Medicine/West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Alan
A
James
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Louise V
LV
Wain
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Martin D
MD
Tobin
D000328:Adult; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*; D012119:Respiration / Q000235:genetics*; D012129:Respiratory Function Tests; D018570:Risk Assessment; D012307:Risk Factors; D013147:Spirometry; D013997:Time Factors; D014904:Western Australia
COPD epidemiology; COPD ÀÜ Mechanisms; Lung Physiology; Respiratory Measurement