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

By Junxi Liu, Rebecca Richmond, Jack Bowden, Ciarrah Barry, Hassan S Dashti, Iyas Daghlas, Jacqueline M. Lane, Samuel E Jones, Andrew R. Wood, Timothy M Frayling, Alison K. Wright, Matthew J Carr, Simon G Anderson, Richard Emsley, David Ray, Sian Ellard, Richa Saxena, Deborah A Lawlor, Martin K. Rutter

Posted 20 Dec 2020
medRxiv DOI: 10.1101/2020.12.18.20224733

ObjectiveTo examine the effects of sleep traits on glycated haemoglobin (HbA1c). DesignObservational multivariable regression (MVR), one-sample Mendelian randomization (1SMR), and two-sample summary data Mendelian randomization (2SMR). SettingUK Biobank (UKB) prospective cohort study and genome-wide association studies from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC). ParticipantsIn 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. ExposuresSelf-reported insomnia frequency (usually vs sometimes or rarely/never); sleep duration: 24-hour sleep duration (hours/day); short sleep ([≤]6 hours vs 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 measureHbA1c in standard deviation (SD) units. ResultsAcross 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. ConclusionsThis 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. SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIIn observational data, insomnia, short sleep duration, and evening preference are associated with higher risk for type 2 diabetes. C_LIO_LIMendelian randomization (MR) studies have not found evidence of a causal effect of short sleep on type 2 diabetes or glycaemic traits but have indicated an effect of insomnia on type 2 diabetes. It is unclear whether insomnia influences HbA1c levels, a marker of long-term hyperglycaemia, in the general population. C_LIO_LIRecently identified genetic variants robustly associated with insomnia, sleep duration, daytime sleepiness, napping, and chronotype can be used in MR studies to explore causal effects of these sleep traits on HbA1c levels. C_LI What this study addsO_LIThis study suggests that a higher frequency of insomnia increases HbA1c levels in the general population and after excluding people with diabetes. C_LIO_LIWe found no robust evidence for causal effects of other sleep traits on HbA1c levels. C_LIO_LIThese findings improve our understanding of the impact of sleep traits on HbA1c levels and have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycaemia and prevent diabetes. C_LI

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