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.
Authors
- Rita de Cássia Calderaro Coelho (ORCID: https://orcid.org/0000-0003-1609-776X)
- Juliana Carla Gomes Rodrigues (ORCID: https://orcid.org/0000-0003-1665-3535)
- Ândrea Ribeiro‐dos‐Santos (ORCID: https://orcid.org/0000-0001-7001-1483)
- Ana Caroline Alves da Costa (ORCID: https://orcid.org/0009-0001-7803-3019)
- Natasha Monte (ORCID: https://orcid.org/0000-0003-4061-5045)
- Giovanna Gilioli da Costa Nunes (ORCID: https://orcid.org/0009-0002-9005-0281)
- Sandro J. de Souza (ORCID: https://orcid.org/0000-0002-1012-3237)
- Rommel Mário Rodríguez Burbano (ORCID: https://orcid.org/0000-0002-4872-234X)
- Sidney Emanuel Batista dos Santos (ORCID: https://orcid.org/0000-0002-8622-9417)
- Tatiane Carinta de Souza (ORCID: https://orcid.org/0009-0001-9131-0455)
- Marianne Rodrigues Fernandes (ORCID: https://orcid.org/0000-0002-1396-3442)
- Ney Pereira Carneiro dos Santos (ORCID: https://orcid.org/0000-0001-8087-7037)
- Kaio Evandro Cardoso Aguiar (ORCID: https://orcid.org/0009-0004-7751-2693)
- André Maurício Ribeiro dos Santos (ORCID: https://orcid.org/0000-0002-7005-3576)
- Aline Pasquini Santos (ORCID: https://orcid.org/0009-0005-0787-2690)
Institutions
- Instituto Federal do Rio Grande do Norte (BR)
- Universidade Federal do Rio Grande do Norte (BR)
- Instituto Federal de Educação, Ciência e Tecnologia do Pará (BR)
- Universidade Federal do Pará (BR)
Publication Details
- Journal
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics
- Published
- 2025-10-07
- DOI
- https://doi.org/10.1002/ajmg.b.33064
- Primary Topic
- Attention Deficit Hyperactivity Disorder
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Universidade Federal do Pará
- Universidade Federal do Rio Grande do Norte