Objective
Major Depressive Disorder (MDD) is a multifactorial psychiatric disease influenced by a combination of genetic and environmental factors. Among the genes linked to MDD, the Melanocortin 1 Receptor (MC1R), Catechol-O-Methyltransferase (COMT), Brain-Derived Neurotrophic Factor (BDNF), and the serotonin transporter (5-HTT) are of particular interest due to their critical roles in stress regulation and neural function.  Despite their biological significance, the contribution of specific polymorphisms within these genes to MDD risk remains understudied. 

Methods
This retrospective observational case-control study included 87 Colombian patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).  The control group comprised Latino/admixed individuals without, sourced from the gnomAD v2.1.1 database. The complete coding region of the MC1R gene and three polymorphisms: 5-HTTLPR Insertion/Deletion 44 bp, BDNF-c.196G>A, and COMT-c.472G>A   were genotyped using PCR and Sanger sequencing. 

Results
The polymorphisms rs885479 and rs4680 were identified as protective factors against MDD, while the polymorphisms rs796296176, rs779504604, rs1805005 were associated with an increased risk of developing MDD (OR:22.87, OR:51.26, OR: 1.97, respectively).

Conclusions
Several of the analyzed polymorphisms (rs796296176, rs779504604, rs1805005) increase the risk for MDD. Notably, we provide novel evidence of these polymorphisms in MC1R as a risk to MDD.