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

## TL;DR

This review explores how genetic variations contribute to depression, focusing on their roles in brain function and stress response.

## Contribution

The paper synthesizes well-replicated and emerging genetic findings in depression, emphasizing biological pathways and translational applications.

## Key findings

- Genetic variants in serotonergic, dopaminergic, and stress-response pathways are linked to depression.
- Polymorphisms in BDNF, COMT, FKBP5, and CRHR1 influence neuroplasticity and HPA axis regulation.
- Polygenic and epigenetic interactions may explain clinical heterogeneity in major depressive disorder.

## Abstract

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.