Postpartum depressive symptom (PDS) is a common psychological and mental disorder after giving birth. Our previous studies showing the application of dexmedetomidine, an α₂-AR agonist, can significantly improve maternal sleep, as well as relieve and reduce the incidence of PDS. This study investigated the association between α₂ _A AR gene polymorphisms and PDS. A total of 568 cesarean section patients were enrolled; the incidence of PDS is 18.13% (103 with PDS, 465 with non-PDS). The Edinburgh Postpartum Depression Scale score ≥10 was used to diagnose PDS at 42 days after delivery. The single-nucleotide polymorphisms of α_2AR were sequenced by pyrosequencing. The effect of rs13306146 A > G polymorphism on α_2AR transcription and the regulation of miR-646 on α_2AR expression were assessed by dual luciferase reporter assays or gene transfection. Increased stress during pregnancy, poor relationship between mother-in-law and daughter-in-law, spousal relationship, domestic violence, antenatal depression, self-harm ideation, and stressful life events were all associated with increased PDS incidence (p < 0.05). The logistic regression analysis found that the α_2AAR rs13306146 polymorphism was associated with PDS after adjusting confounding variables. The transcriptional function of the α_2AAR rs13306146 A allele was decreased compared with the G allele, and the α_2AAR expression level was correspondingly decreased (p < 0.05), as the strongest binding ability of miR-646 to the α_2AAR rs13306146 AA genotype. The effect of α_2AAR rs13306146 A > G polymorphism may change the binding ability of miR-646 at the 3'UTR of the α_2AAR gene, affecting the expression of α_2AAR. This study supports the involvement of the norepinephrine system in the pathogenesis of PDS. Genotypes of α_2AAR may be novel and useful biomarkers for PDS.

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