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 calculated for the joint effect of 26 known regions on baseline and longitudinal change 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=4.44x10-16 54 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. Thirty-nine 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 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. What is the key question? Do genetic regions associated with cross-sectional lung function also show association with rate of decline? What is the bottom line? Twenty six regions associated with cross-sectional lung function in adults – many of them associated with COPD risk – were not associated with rate of decline in lung function. Why read on? These findings provide an important insight into the possible pathways through which known genetic regions influence lung function and risk of COPD. ; This work was supported by the Medical Research Council [G0902313 to MDT] and Pfizer. This paper presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. The Busselton Health Study acknowledges the support of the National Health and Medical Research Council of Australia, the Government of Western Australia (Health Department, Sir Charles Gairdner Hospital, PathWest and Healthway), Pfizer and the volunteers and participants of the study. The Copenhagen City Heart Study was supported by Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital and the Danish Heart Foundation. We thank staff and participants of the Copenhagen City Heart Study for their contribution. The Lung Health Study (LHS) I was supported by the National Institutes of Health [contract NIH/N01- HR-46002] and genome-wide association genotyping and analysis of LHS was supported by the National Institutes of Health as part of the Gene Environment Association Studies (GENEVA) [U01HG004738]. ; Peer-reviewed ; Post-print