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

ABSTRACT 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 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 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. SUMMARY BOX What is already known on this topic In observational data, insomnia, short sleep duration, and evening preference are associated with higher risk for type 2 diabetes. Mendelian 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. Recently 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. What this study adds This study suggests that a higher frequency of insomnia increases HbA1c levels in the general population and after excluding people with diabetes. We found no robust evidence for causal effects of other sleep traits on HbA1c levels. These 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.