Healthy sleep, proteomic signatures, and incident depression: associations accounting for genetic risk in an adult cohort.
Peng S, Guo Y, et al. • The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry • 2026
Healthy sleep patterns and their plasma proteomic signature are associated with reduced depression risk, highlighting targets for prevention and mechanistic research.
Key Findings
Results
Higher overall healthy sleep pattern scores showed a dose-dependent reduced risk of incident depression after adjustment for covariates and polygenic risk scores.
HR per 1-score increment = 0.81 (95% CI: 0.77–0.85)
The association was dose-dependent, meaning each additional healthy sleep factor incrementally reduced depression risk
Adjustment included both standard covariates and polygenic risk scores (PRS) for depression
Among 39,702 depression-free UK Biobank participants at baseline
Results
During a median follow-up of 14.5 years, 1,941 out of 39,702 participants developed depression.
Median follow-up duration was 14.5 years
1,941 incident depression cases occurred
The study population was drawn from the UK Biobank and was free of depression at baseline
Five healthy sleep factors were assessed at baseline
Results
496 plasma proteins were identified as linked to healthy sleep patterns, and a composite proteomic signature of 181 proteins was derived.
Linear and LASSO regression were used to identify sleep-associated proteins and construct proteomic signatures
496 proteins were initially linked to healthy sleep patterns
A refined composite signature of 181 proteins was constructed for downstream analyses
Plasma proteomic profiles were assessed alongside sleep, PRS, brain imaging, and covariates
Results
The 181-protein proteomic signature was inversely associated with depression risk across all polygenic risk score groups.
The inverse association between the proteomic signature and depression risk held regardless of genetic susceptibility level
Analyses were stratified or adjusted by PRS groups for depression
This finding suggests the proteomic signature's protective association is not confined to low genetic risk individuals
Results
The proteomic signature mediated 15.8% of the association between healthy sleep patterns and incident depression.
Formal mediation analysis was conducted to assess the indirect pathway from sleep to depression through plasma proteins
The mediated proportion was 15.8%
This indicates that while proteins partially explain the sleep-depression relationship, a substantial portion of the association operates through other mechanisms
Results
The proteomic signature was correlated with brain regions involved in emotion regulation.
Brain imaging data from UK Biobank participants were used to assess structural correlations
The proteomic signature showed correlations specifically with emotion regulation brain regions
This provides a potential neurobiological link between sleep-associated proteins and depression risk
What This Means
This research suggests that people who maintain healthier sleep habits — such as appropriate sleep duration, good sleep quality, and regular sleep timing — have a meaningfully lower risk of developing depression over time, even when accounting for their genetic predisposition to the condition. Using data from nearly 40,000 adults followed for an average of 14.5 years, researchers found that each additional healthy sleep factor reduced depression risk by roughly 19%, and this relationship was consistent regardless of whether participants had high or low genetic risk for depression.
The study also found that healthy sleep is associated with distinctive patterns of proteins circulating in the blood. By identifying 181 proteins that together form a 'proteomic signature' of healthy sleep, the researchers showed that this protein pattern itself is linked to lower depression risk, and that it accounts for about 15.8% of the protective effect that sleep has on depression. These proteins were also correlated with brain regions involved in regulating emotions, suggesting a possible biological pathway connecting sleep to mental health.
This research matters because it identifies specific biological molecules (proteins) that may help explain why sleep protects against depression, and it does so in a way that holds true even for people who are genetically vulnerable to depression. These proteins could potentially serve as targets for future treatments or as biomarkers to identify who might benefit most from sleep-focused prevention strategies for depression.
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Peng S, Guo Y, Wang W, Jiang G, Liu Q, Lu C, et al.. (2026). Healthy sleep, proteomic signatures, and incident depression: associations accounting for genetic risk in an adult cohort.. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. https://doi.org/10.1080/15622975.2026.2656652