Extended Data Fig. 2: Sleep Chart delineates U-shaped associations between sleep duration and 342 organ-enriched proteins.

a) Sleep duration was associated with 342 organ-enriched plasma proteins (x-axis) using the GAM model. These organ/tissue-enriched proteins were defined in our previous study² via resources from the Human Protein Atlas (https://www.proteinatlas.org/) project. Non-grey coloured proteins indicate proteins with significant associations after Bonferroni correction for multiple comparisons across all available proteins (two-sided P < 0.05/2923 for all available proteins). The y-axis shows the effective degrees of freedom (EDF), quantifying the degree of nonlinearity (e.g., U-shaped associations), with representative proteins annotated for each organ. b) Representative U-shaped relationship between the FGFR2 protein and sleep duration. The solid curves depict estimated protein, while shaded bands represent the 95% confidence interval (CI). c-d) Protein-protein interaction (PPI) network was conducted using STRING v12.0 (https://string-db.org/) to examine the functional relationships among 14 immune-enriched and 29 hepatic-enriched proteins. STRING integrates evidence from experimental data, computational predictions, and literature text mining, enabling the PPI network to reveal how these proteins may functionally interact within and across biological pathways, potentially offering insights into shared mechanisms and tissue-specific processes. e) We performed protein set enrichment analysis (PSEA) using STRING for organs with more than 9 significant proteins (i.e., the hepatic and immune) to identify over-represented Gene Ontology (GO) terms across biological processes, molecular functions, and cellular components. Icon sizes in the visualization reflect the statistical significance, represented by the -log₁₀(FDR-corrected P). The strength measurement (x-axis) is a log-scale enrichment ratio that shows the magnitude of enrichment. We group distinct GO terms along the y-axis by associating each biological pathway with potential sleep-related hypotheses informed by prior literature, such as the immune activation and inflammation hypothesis⁸⁶ or the Extracellular signalling and vesicle transport hypothesis⁸⁷.