Genetic evidence for the causal effects of C-reactive protein on self-reported habitual sleep duration

Inflammatory responses to acute stimuli are proposed to regulate sleep, but the relationship between chronic inflammation and habitual sleep duration is elusive. Here, we study this relation using genetically predicted level of chronic inflammation, indexed by CRP and IL6 signaling, and self-reported sleep duration. By Mendelian randomization analysis, we show that elevated CRP level within <10 mg/L has a homeostatic effect that facilitates maintaining 7-8 h sleep duration per day - making short-sleepers sleep longer (p = 2.42 × 10-2) and long-sleepers sleep shorter (1.87 × 10-7); but it is not associated with the overall sleep duration (p = 0.17). This homeostatic effect replicated in an independent CRP dataset. We observed causal effects of the soluble interleukin 6 receptor and gp130 on overall sleep duration (p = 1.62 × 10-8, p = 2.61 × 10-58, respectively), but these effects disappeared when CRP effects were accounted for in the model. Using polygenic score analysis, we found that the homeostatic effect of CRP on sleep duration stems primarily from the genetic variants within the CRP gene region: when genetic variants outside of this region were used to predict CRP levels, the opposite direction of effect was observed. In conclusion, we show that elevated CRP level may causally facilitate maintaining an optimal sleep duration that is beneficial to health, thus updating our current knowledge of immune regulation on sleep.