Causal relationships between insomnia and blood metabolome: a Mendelian randomization study with mouse experimental validation.

Higher oleate levels were causally associated with lower insomnia risk in the Mendelian randomization analysis.

• The association was statistically significant (β: -5.99, p = 0.01).
• The reverse direction was not supported: insomnia did not alter oleate levels in the human MR analysis.
• Data came from two large GWAS: one on insomnia (336,965 participants) and one on metabolites (7,824 participants).
• Genetic variants were used as instrumental variables to infer causal direction.

Insomnia causally increased blood glucose and mannose levels in the Mendelian randomization analysis.

• Insomnia increased glucose levels (β: 0.18, p = 0.002).
• Insomnia increased mannose levels (β: 0.11, p = 0.02).
• These findings suggest insomnia has downstream metabolic consequences on carbohydrate-related metabolites.
• Analysis used bidirectional MR design to distinguish cause from effect.

Insomnia causally influenced six lipids and four amino acids in the Mendelian randomization analysis.

• Beyond glucose and mannose, insomnia was found to affect a total of six lipid metabolites.
• Insomnia also influenced four amino acid metabolites.
• The specific identities of these lipids and amino acids are detailed in the full paper beyond what is reported in the abstract.
• These findings were derived from the forward-direction MR (insomnia as exposure, metabolites as outcome).

In a mouse chronic sleep deprivation model, blood and fecal oleate levels were significantly reduced.

• 12 mice were divided into control and chronic sleep deprivation groups (n = 6 each).
• Sleep deprivation lasted 32 days before blood and fecal metabolite analysis.
• Blood oleate levels were significantly lower in sleep-deprived mice (p = 0.007).
• Fecal oleate levels were also reduced in sleep-deprived mice (p = 0.05).
• This mouse result appears to contradict the human MR finding that insomnia does not alter oleate, suggesting a complex relationship.

Sleep deprivation in mice raised blood glucose and mannose levels, consistent with the human Mendelian randomization findings.

• Both glucose and mannose were elevated in sleep-deprived mice compared to controls (p = 0.001 for both).
• This validates the human MR finding that insomnia causally increases glucose (β: 0.18, p = 0.002) and mannose (β: 0.11, p = 0.02).
• The mouse model used chronic sleep deprivation over 32 days.
• Group sizes were n = 6 per group.

Chronic sleep deprivation in mice lowered blood corticosterone levels.

• Corticosterone, a stress hormone, was significantly reduced in sleep-deprived mice (p = 0.03).
• This hormonal change was observed after 32 days of chronic sleep deprivation.
• This finding suggests sleep deprivation is associated with notable hormonal disruption beyond metabolic changes.
• n = 6 per group.

Fecal 4-aminobutyric acid (GABA) was decreased in sleep-deprived mice.

• Fecal 4-aminobutyric acid levels were significantly lower in the chronic sleep deprivation group (p = 0.01).
• 4-aminobutyric acid is also known as gamma-aminobutyric acid (GABA), a key inhibitory neurotransmitter.
• This was measured in fecal samples after 32 days of sleep deprivation.
• The reduction suggests sleep deprivation may affect gut-derived GABAergic signaling.

The study employed a bidirectional Mendelian randomization design using large-scale GWAS data to infer causal relationships between metabolites and insomnia.

• The insomnia GWAS included 336,965 participants.
• The metabolomics GWAS included 7,824 participants.
• Genetic variants associated with metabolites and insomnia were used as instrumental variables.
• Bidirectional MR tests both metabolites as causes of insomnia and insomnia as a cause of metabolite changes.
• Findings were validated using a mouse chronic sleep deprivation model over 32 days with blood and fecal metabolite profiling.