The creative mind in the shadow of depressive symptoms: Epigenetic variation in HPA axis genes is associated with the link between depressive symptoms and creative personality

This cross-sectional study investigated the relationship between depressive symptoms and creative personality through the lens of epigenetic modifications within Hypothalamic-Pituitary-Adrenal (HPA) axis genes. By analyzing DNA methylation patterns in key HPA axis genes—including corticotropin-releasing hormone (CRH), its receptor (CRHR1), CRH binding protein (CRHBP), melanocortin 2 receptor (MC2R), steroidogenic acute regulatory protein (STAR), FK506 binding protein 5 (FKBP5), and the glucocorticoid receptor (NR3C1), we examined how methylation variation was associated with the depressive symptoms-creativity link in 371 participants (190 women, 181 men). Our findings revealed that among individuals with methylation patterns putatively associated with reduced HPA axis activity, higher depressive symptoms were positively associated with creative personality, suggesting that in this biological context, introspective aspects of depressive symptoms may coincide with creative propensities. Conversely, among individuals with methylation patterns putatively associated with heightened HPA axis activity, higher depressive symptoms were negatively associated with creative personality. These results suggest that the association between depressive symptoms and creativity is not uniform but differs based on methylation variation in genes involved in stress response regulation. The findings highlight the potential role of HPA axis-related biological factors in understanding individual differences in the depression-creativity relationship, though the cross-sectional design precludes causal inference.