Molecular Profiling of Genes Associated With Methylphenidate Pathway Therapy and Discovery of New Variants in Amazonian Amerindian Populations.

In Attention Deficit Hyperactivity Disorder (ADHD), methylphenidate is one of the most widely used drugs, in which patient response significantly impacts prognosis. This study aimed to characterize the molecular profile of 10 genes associated with methylphenidate therapy. Whole-exome sequencing of 64 indigenous individuals from 12 different indigenous populations in the Amazon was used. A total of 143 genetic variants were identified, of which 123 were analyzed. Among these, three novel and population-specific variants were found, all with modifying impact, located in the ADGRL3 and ADRA2A genes. In addition, we identified a high-impact variant in the COMT gene, which exhibited statistical significance in the INDG population compared to other groups, along with five variants with moderate impact and 31 with modifying impact. Our findings highlight the unique genetic profile of indigenous populations in the Brazilian Amazon and provide valuable insights to optimize ADHD management and treatment strategies. This study contributes to improving therapeutic responses to methylphenidate and supports the development of precision medicine guidelines.