1. Research Questions: This study investigates the extent to which chronic circadian misalignment-manifested through shift work and sleep-wake fragmentation-impairs female reproductive longevity and endocrine homeostasis. Specifically, it addresses: (i) the degree of functional impairment caused by rhythm disruption to the hypothalamic-pituitary-gonadal (HPG) axis; (ii) how the “Gut-Brain-Metabolic-Gonadal axis,” proxied by the Dietary Index for Gut Microbiota (DI-GM), psychosocial stress, and NMR-derived metabolic signatures, mediates this decline; and (iii) whether these associations are driven by direct causal pathways or shared genetic pleiotropy.
2. Research Objectives: By integrating multi-dimensional data from the UK Biobank, this project aims to fulfill four primary objectives: (i) Phenotypic Mapping, utilizing objective accelerometry-derived indices to systematically characterize associations with PCOS, infertility, and menopausal timing; (ii) Mediation Quantification, assessing the contribution of the gut microbiome (via DI-GM), neuropsychiatric traits, and systemic metabolic profiles; (iii) Causal Inference, employing multivariable Mendelian Randomization (MVMR) to disentangle the molecular clock from the gonadal axis; and (iv) Risk Stratification, developing a predictive framework to identify vulnerable populations for early reproductive intervention.
3. Scientific Rationale: The sensitivity of the HPG axis to biological clock cues necessitates a large-scale investigation into the systemic pathways linking environmental desynchrony to reproductive aging. To overcome the lack of direct metagenomic sequencing, we utilize the Dietary Index for Gut Microbiota (DI-GM) as a validated proxy for microbial health, integrated with Nuclear Magnetic Resonance (NMR) spectroscopy data. Leveraging the massive statistical power of the UK Biobank, this approach allows for the high-dimensional mapping
