Exploring the Relationship Between Caffeine Consumption, Caffeine Metabolism, and Sleep Behaviours: A Mendelian Randomisation Study.

Higher consumption of caffeinated beverages is associated with disturbed sleep patterns. Using genetic variants as proxies for caffeine consumption, caffeine metabolism, and sleep traits, we investigated whether this association reflects a direct effect of caffeine. Genetic variants associated with caffeine consumption (n = 407,072), caffeine metabolism (n = 9876), chronotype (n = 449,734), daytime napping (n = 452,633), daytime sleepiness (n = 452,071), getting up in morning (n = 385,949), insomnia (n = 453,379), and sleep duration (n = 446,118) identified in individuals from several studies, including the UK Biobank, were used to explore bi-directional causal relationships between caffeine and sleep using a series of univariable Mendelian Randomisation analyses. We used multivariable Mendelian Randomisation to explore the direct effects of caffeine consumption on sleep behaviours while adjusting for metabolism and vice versa. Higher consumption decreased daytime sleepiness (β_univariable = -0.044, 95% CI [-0.065, -0.023], p < 0.001; β_{multivariable} = -0.034, 95% CI [-0.058, -0.009], p = 0.010), while faster caffeine metabolism, indicative of less caffeine exposure per beverage consumed, decreased the likelihood of daytime napping (β_univariable = -0.024, 95% CI [-0.037, -0.011], p < 0.001; β_{multivariable} = -0.021, 95% CI [-0.042, 0.000], p = 0.051). Being an evening person decreased caffeine consumption (β_univariable = -0.044, 95% CI [-0.078, -0.010], p = 0.010). Caffeine consumption/metabolism was not causally related to sleep duration or insomnia. We found no clear evidence for effects of caffeine consumption/metabolism on sleep among non-current caffeine consumers when assessing possible pleiotropy. Overall, sleep appears to be impacted by caffeine in a way that influences daytime alertness rather than night-time sleep characteristics. However, the presence of weak instruments for caffeine metabolism and significant heterogeneity warrants further research with larger and diverse samples to better understand the causal pathway between caffeine and sleep.