Assessing the causal role of sleep traits on glycated haemoglobin: a Mendelian randomization study

Objective To examine the effects of sleep traits on glycated haemoglobin (HbA1c). Design Observational multivariable regression (MVR), one-sample Mendelian randomization (1SMR), and two-sample summary data Mendelian randomization (2SMR). Setting UK Biobank (UKB) prospective cohort study and genome-wide association studies from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC). Participants In MVR and 1SMR, participants were adults (mean (SD) age 57 (8) years; 54% female) from the UKB (n=336,999); in 2SMR, participants were adults (53 (11) years; 52% female) from MAGIC (n=46,368). All participants were adults of European ancestry. Exposures Self-reported insomnia frequency (usually vs sometimes or rarely/never); sleep duration: 24-hour sleep duration (hours/day); short sleep (≤6 hours v s 7-8 hours) and long sleep (≥9 hours vs 7-8 hours); daytime sleepiness and daytime napping (each consisting of 3 categories: never/rarely, sometimes, usually); chronotype (5 categories from definite morning to definite evening preference). Main outcome measure HbA1c in standard deviation (SD) units. Results Across MV, 1SMR, 2SMR, and their sensitivity analyses we found a higher frequency of insomnia (usually vs sometimes or rarely/never) was associated with higher HbA1c (MVR: 0.053 SD units, 95% confidence interval (0.046 to 0.061), 1SMR: 0.52, (0.42 to 0.63), 2SMR: 0.22, (0.10 to 0.35)). Results remained significant but point estimates were somewhat attenuated after excluding people with diagnosed diabetes. For other sleep traits, there was less consistency with significant associations when using some, but not all methods. Conclusions This study suggests that insomnia increases HbA1c levels. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycaemia and prevent diabetes. What is already known on this topic What this study adds ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at www.iemje.org/coi_disclosure.pdf and declare: MKR reports receiving research funding from Novo Nordisk, consultancy fees from Novo Nordisk and Roche Diabetes Care, and modest owning of shares in GlaxoSmithKline all unrelated to this work. JB reports receiving consultancy fees from Novartis unrelated to this work. DAL has received support from Roche Diagnostics and Medtronic Ltd for research unrelated to that presented here. No support from any organisation that might have an interest in the submitted work in the previous three years; no financial relationships with any organisation that might have an interest in the submitted work in the previous three year; no other relationship or activities that could appear to have influenced the submitted work. ### Funding Statement This work is supported by a Diabetes UK grant (17/0005700), which funds JL, AW and SJ s salary. JL, RCR and DAL 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 DAL s contribution to this paper was support by a grant from the British Heart Foundation (AA/18/7/34219). DAL is a NIHR Senior Investigator (NF-0616-10102). RCR is a de Pass Vice Chancellor s research fellow at the University of Bristol. HSD and RS are funded by the National Institute of Health ((R01DK107859). RS is funded by the National Institute of Health (R01DK105072). RS is awarded the Phyllis and Jerome Lyle Rappaport Massachusetts General Hospital Research Scholar Award. JB is funded by an Establishing Excellence in England (E3) grant awarded to the University of Exeter. DWR MRC programme grant MR/P023576/1. DWR is a Wellcome Investigator, Wellcome Trust (107849/Z/15/Z, 107849/A/15/Z). CB is supported by the Wellcome Trust via a PhD [218495/Z/19/Z]. ### 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: UK Biobank has received ethical approval from the UK National Health Service s National Research Ethics Service (ref 11/ NW/0382). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 R scripts for the MVR, 1SMR, 2SMR, and other relevant sensitivity analyses are available on GitHub at: https://github.com/jamesliu0501/sleeptraits\_glyacemic\_MRproject.git. For statistical code relating to the individual level data analysis in UK Biobank, please contact the corresponding author via ieu_james.liu@bristol.ac.uk [https://github.com/jamesliu0501/sleeptraits\_glyacemic\_MRproject.git][1] [1]: https://github.com/jamesliu0501/sleeptraits_glyacemic_MRproject.git