Genetic and Epigenetic Insights in Major Depression

Clinical Depression is a prevalent, disabling psychiatric disorder with rising global impact,especially in low- and middle-income countries. Traditionally defined by affective andcognitive symptoms, Major Depressive Disdorder is now understood as a heterogeneousdisorder influenced by both biological and environmental factors. This review explored theneurobiological and genetic foundations of MDD, emphasizing key molecular pathwaysincluding serotonergic signaling, neuroinflammation, neurotrophic support, and stressreactivity. Candidate genes such as SLC6A4, BDNF, and FKBP5 are examined, alongsideemerging insights into gene-environment interactions (G×E) and epigenetic modulation ofdepression risk. This review also discussed recent advances in polygenic risk scoring,microbiota-brain interactions, and immune-metabolic frameworks that are reshapingunderstanding of depression etiology. Special attention is given to the underrepresentation ofAfrican populations in psychiatric genetics, highlighting the importance of diversity inbiomarker discovery and treatment development. The review advocated for a systems-based,integrative approach that accounts for sex differences, environmental context, and genomicvariability. Future research directions include the use of multi-omics, culturally inclusive studydesigns, and biomarker-informed strategies for prevention and treatment. By bridgingneurobiology with real-world diversity, this review underscores the importance of translationalpsychiatry in addressing the evolving global burden of MDD.