Cerebrospinal Fluid, Plasma Tryptophan, Kynurenine, and Kynurenate with Sleep Phenotypes: A Bidirectional Mendelian Randomization Analysis.

Abstract

Sleep is crucial for physiological regulation in humans and essential for sustaining life. Although melatonin, an intermediate in the tryptophan (TRP)-serotonin pathway, is widely explored as a modulator of the sleep-wake cycle, the association of TRP-kynurenine (KYN) pathway with sleep or circadian timing remains poorly understood. This work employed Mendelian randomization (MR) to examine possible causal links between sleep-associated phenotypes and metabolites in the TRP-KYN pathway. We applied data derived from genome-wide association research of TRP, KYN, and kynurenate (KYNA), the key metabolites in this pathway, and investigated sleep-related phenotypes extensively, including both self-reported phenotypes and those objectively estimated with an accelerometer. We evaluated the associations between 11 sleep-related phenotypes and plasma and cerebrospinal fluid (CSF) metabolites via two-sample bidirectional MR analysis. The forward MR analysis revealed a positive association between genetically predicted plasma KYN levels and L5 timing, with an OR of 1.194 (95% CI: 1.025-1.389; P = .022) utilizing the inverse variance weighted (IVW) approach. This effect direction was consistent across all MR methods, without evident horizontal pleiotropy or heterogeneity. However, this association was no longer significant after false discovery rate (FDR) correction and should therefore be interpreted as suggestive. In reverse MR analysis, sleep-related phenotypes showed no significant causal effects on CSF and plasma metabolites. To complement the population-level MR analyses, we performed an exploratory, hypothesis-generating in vitro experiment in Rat-1 fibroblasts and found that 200 μM L-kynurenine continuously upregulated Bmal1 mRNA at several circadian time points. Overall, our findings provide suggestive evidence that genetically predicted higher plasma kynurenine are associated with delayed L5 timing, which requires confirmation through replication and mechanistic studies.