The role of accelerometer-derived sleep traits on glycated haemoglobin and glucose levels: a Mendelian randomization study

Study Objectives Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar results observed in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not other sleep traits, on glycated haemoglobin (HbA1c). Our aims were a) to explore potential effects of accelerometer-derived sleep traits on HbA1c and glucose levels and b) to determine genetic correlations across accelerometer-derived and self-reported sleep traits. Methods We used MR methods to explore effects of accelerometer-derived sleep traits (duration, mid-point least active 5-hours, mid-point most active 10-hours, sleep fragmentation, and efficiency) on HbA1c in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 149,054). Cross-trait linkage disequilibrium score regression was also applied to determine genetic correlations across all accelerometer-derived and self-reported sleep traits and HbA1c/glucose. Results Main and sensitivity MR analyses showed no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. Conclusions Taken together, these findings suggested accelerometer-derived sleep traits do not causally affect HbA1c levels, and accelerometer-derived measures of sleep duration and sleep quality might not simply be ‘objective’ measures of self-reported sleep duration and insomnia, but rather captured different underlying sleep characteristics. Statement of Significance Self-reported and accelerometer-derived sleep disturbance is associated with increased risk of hyperglycaemia and type 2 diabetes in observational analyses. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not other self-reported sleep traits, on glycated haemoglobin (HbA1c). This MR study showed little evidence supporting an effect of any accelerometer-derived sleep trait on HbA1c or glucose, but a potential non-linear (e.g., U-shaped) effect cannot be ruled out. The genetic correlation suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different exposures. ### Competing Interest Statement J.B reports receiving consultancy fees from Novartis unrelated to this work. D.A.L has received support from Roche Diagnostics and Medtronic Ltd for research unrelated to that presented here. No other potential conflicts of interest of other co-authors relevant to this article were reported. ### Funding Statement This work is supported by a Diabetes UK grant (17/0005700), which funds J.L, A.K.W, and S.E.J s salary. J.L, R.C.R, E.L.A, and D.A.L work in a unit that is funded by the University of Bristol and the UK Medical Research Council (MC\_UU\_00011/1 and MC\_UU\_00011/6) and D.A.L s contribution to this paper was supported by a grant from the British Heart Foundation (AA/18/1/34219) an NIHR Senior Investigator (NF-0616-10102) and BHF Chair in Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003). R.C.R is a de Pass Vice Chancellor s research fellow at the University of Bristol. H.S.D. is funded by the National Institutes of Health (K99HL153795). R.S is funded by the National Institute of Health (R01DK107859 and R01DK105072). R.S is awarded the Phyllis and Jerome Lyle Rappaport Massachusetts General Hospital Research Scholar Award. J.B is funded by an Establishing Excellence in England (E3) grant awarded to the University of Exeter. D.W.R is funded by MRC programme grant (MR/P023576/1), and is a Wellcome Investigator, Wellcome Trust (107849/Z/15/Z and 107849/A/15/Z), and NIHR Oxford Health Biomedical Research Centre (NIHR203316). C.S.B is supported by the Wellcome Trust via a Ph.D. (218495/Z/19/Z). S.D.K is supported by the NIHR Oxford Biomedical Research Centre. E.L.A is funded by a UKRI Future Leaders Fellowship (MR/W011581/1). This research was supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. These funders did not have any role in the study design, analyses or interpretation of results. The views expressed in the paper are those of the authors and not necessarily any acknowledged funders. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Biobank has received ethical approval from the U.K. National Health Service National Research Ethics Service (London, U.K.) (ref 11/NW/0382). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All UK Biobank data are available to the research community via an application, with full details of this process provided on the study website (). Summary data on sleep traits and glycaemic traits are available unrestricted and can be downloaded, as we have for this study from the Sleep Disorder Knowledge Portal and the MAGIC from [www.magicinvestigators.org][1] respectively. R scripts for the key analyses are available on GitHub at: . For statistical code relating to the individual level data analysis in UK Biobank, please contact the corresponding author via ieu_james.liu{at}bristol.ac.uk. [1]: https://www.magicinvestigators.org