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This study aimed to characterize the molecular profile of 10 genes associated with methylphenidate therapy. Whole\u2010exome 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\u2010specific variants were found, all with modifying impact, located in the ADGRL3 and ADRA2A genes. In addition, we identified a high\u2010impact 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.<\/jats:p>","DOI":"10.1002\/ajmg.b.33064","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:15:53Z","timestamp":1759900553000},"page":"291-299","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Profiling of Genes Associated With Methylphenidate Pathway Therapy and Discovery of New Variants in Amazonian Amerindian Populations"],"prefix":"10.1002","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0787-2690","authenticated-orcid":false,"given":"Aline Pasquini","family":"Santos","sequence":"first","affiliation":[{"name":"Research Center of Oncology Federal University of Par\u00e1 Bel\u00e9m  Bel\u00e9m 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