Pharmacogenomics of Major Depressive Disorder in Indigenous Amazonian Populations

Major depressive disorder is a highly prevalent psychological disorder worldwide and its main treatment is the use of Selective Serotonin Reuptake Inhibitors. However, few studies have demonstrated the relationship between the presence of genetic variants in pharmacogenes and the efficacy of these drugs, especially in populations with a unique genetic profile, such as the Indigenous peoples of the Amazon. Our study characterized the molecular profile of nine genes related to drug administration, metabolization, distribution, and elimination pathways and pharmacodynamic mechanisms of drug response through Whole Exome Sequencing applied in 64 Indigenous located in the Amazon. We compared the allele frequencies of the variants in Indigenous peoples and other world populations using Fisher's exact test carried out in RStudio v.3.5.1. We identified a total of 125 variants, of which 6 are possible new variants in our population on the HTR2A, HTR2C, CYP2D6, and CYP1A2 genes. At least 9 variants showed a significant difference in the Indigenous population compared with other populations worldwide. Our study reaffirms the unique genetic profile of the Brazilian Amazon Indigenous population and allows us to contribute population-specific variants that may serve as future pharmacogenomic biomarkers that help in the understanding of the individual genetic profiles of Indigenous people. Although the present study does not evaluate clinical drug response, the characterization of these variants provides a foundation for future studies exploring their potential impact on antidepressant efficacy in Indigenous populations and the application of this knowledge in the development of specific treatment protocols guided by pharmacogenomics.