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

Apr 22, 2026International journal of tryptophan research : IJTR

Links between Sleep Patterns and Levels of Tryptophan and Its Breakdown Products in Fluid and Blood Using Genetic Analysis

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Abstract

Genetically predicted plasma kynurenine levels are associated with an increased odds ratio of 1.194 for delayed L5 timing.

The study examined links between sleep-related traits and metabolites in the tryptophan-kynurenine pathway using Mendelian randomization.
A positive association was observed between plasma kynurenine levels and delayed L5 timing, although it lost significance after correction for false discovery rate.
No significant causal effects were found from sleep-related traits on metabolites in cerebrospinal fluid and plasma.
An exploratory experiment indicated that high levels of kynurenine may influence gene expression linked to circadian rhythms in Rat-1 fibroblasts.
Findings suggest a need for further research to confirm the relationship between kynurenine and sleep timing.

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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; = .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 upregulatedmRNA 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. P Bmal1

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

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