Genetic links between female reproductive milestones and major depressive disorder: evidence from a common genetic factor model

Major depressive disorder (MDD) is more prevalent in women and has been linked to female reproductive timing. However, the genetic mechanisms underlying these associations remain unclear. Reproductive milestones are temporally structured and biologically interrelated, suggesting a shared genetic architecture that may influence MDD susceptibility. Using large-scale genome-wide association study (GWAS)data, we analyzed five key female reproductive milestones and their genetic relationships with MDD. We applied linkage disequilibrium score regression (LDSC), Genomic Structural Equation Modeling (GenomicSEM), Mendelian randomization (MR), and colocalization analyses to characterize the shared genetic architecture between reproductive timing and MDD. A single latent reproductive timing factor showed excellent model fit (CFI = 0.997, SRMR = 0.017, AIC = 41.5). MR analysis further indicated that genetically predicted higher Common Factor scores, reflecting older ages across all five reproductive milestones, were significantly associated with decreased MDD risk (IVW β = −3.05, 95%CI = − 3.825 to − 2.277, p = 1.10 × 10⁻¹⁴). Colocalization identified shared gene expression signals in the hypothalamus and heart-left ventricle, implicating neuroendocrine and cardiovascular pathways. Functional enrichment indicated involvement in synapse organization, cell adhesion, and calcium ion binding. Age at menarche (AAM) emerged as a promising early biomarker for MDD susceptibility. A single latent reproductive timing factor effectively captures the shared genetic architecture across female reproductive milestones and their relationship with MDD risk. These findings deepen understanding of reproductive biology in mental health and offer potential targets for early risk identification and intervention in women. Clinical trail number is not applicable.