The Sex‐ and Age‐Specific Association of AANAT Gene Polymorphisms With the Risk of Major Depressive Disorder in the Chinese Population

The Arylalkylamine N-Acetyltransferase (AANAT) serves as the rate-limiting enzyme in melatonin biosynthesis; dysregulation of the melatonin system has been implicated in major depressive disorder (MDD). This study aimed to investigate the associations between the AANAT gene polymorphisms (rs4238989 and rs3760138) and MDD risk in a Chinese population. A case-control study was conducted involving 502 MDD patients and 504 healthy controls. Peripheral blood samples were collected from all participants, and genotyping for the rs4238989 and rs3760138 was performed using next-generation sequencing. Our results found that the G allele and CG + GG genotypes of AANAT rs4238989 were associated with an increased risk of MDD in males but not in females. Interesting, these significant associations were also found in young males aged 18-35 years but not in middle-aged males aged 36-65 years. However, no significant associations were observed between AANAT rs4238989 or rs3760138 polymorphisms and MDD risk in the overall population. Subgroup analysis by sex did not find an association between the rs3760138 polymorphism and MDD risk. Our findings suggest that the AANAT rs4238989 polymorphism may increase MDD risk in males, specifically in young male adults, and could potentially serve as a biomarker for early identification or a target for personalized treatment strategies in this subgroup.