NPAS2 gene variants modulate the circadian preference-depression link in Major Depressive Disorder: A mediation role of sleep and somatic symptoms

Circadian dysregulation is implicated in Major Depressive Disorder (MDD). This study investigated the mediating roles of sleep disturbances and somatic symptoms in the circadian preference-depression relationship and explored moderating effects of NPAS2 variants in 257 MDD patients. The Hamilton Rating Scale for Depression (HAMD-17,17-item clinician-rated measure of depression severity), Morningness-Eveningness Questionnaire (MEQ, circadian preference scale), Pittsburgh Sleep Quality Index (PSQI, sleep quality measure), and Depression and Somatic Symptoms Scale (DSSS, somatic symptom inventory) were obtained in all subjects. Genotypes of single nucleotide polymorphisms (SNPs) of NPAS2 were determined by the PCR and MassArray SNP sequencing analysis. Spearman's correlation, bootstrap mediation, and moderated mediation analyses revealed that sleep disturbances and somatic symptoms sequentially mediated the circadian preference-depression link (preference→sleep: β = -0.075,p = 0.002; sleep→somatic: β = 0.711,p < 0.001; somatic→depression: β = 0.216,p < 0.001). NPAS2 variants moderated these effects: rs3768984 strengthened eveningness-sleep associations (β = 2.944,p < 0.05), while rs3811561 showed similar amplification (β = 3.942,p < 0.05). Rs3768984 additionally moderated the mediation pathway (β = -0.054,95%CI[-0.09,-0.02]). These findings elucidate mechanistic pathways connecting circadian rhythms and MDD, highlighting NPAS2 as a genetic moderator, which may inform targeted interventions. Future studies could explore circadian genetic influences on personalized depression interventions.