The Genetic Mosaic of Depression: Linking Polymorphisms to Neuroplasticity and Stress Regulation

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review synthesizes current evidence on genetic variants associated with MDD, highlighting well-replicated results while distinguishing exploratory or emerging findings. Key systems reviewed include serotonergic (SLC6A4), neurotrophic (BDNF rs6265 and rs962369), dopaminergic and stress-response pathways (COMT, FKBP5, CRHR1), as well as additional emerging genes such as MAOA, TPH2, and FTO. We evaluate these variants in the context of their biological relevance, including neuroplasticity, neurotransmission, and hypothalamic-pituitary-adrenal (HPA) axis regulation, and discuss how polygenic and epigenetic interactions may shape clinical heterogeneity. This framework not only integrates current genetic knowledge but also outlines potential translational applications, offering perspectives for personalized approaches to diagnosis, prognosis, and treatment in MDD.