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Evidence from neurochemical, pharmacological, and genetic research supports the hypothesis that ADHD involves alterations in neurotransmission, primarily within dopaminergic and noradrenergic systems, with contributions from other neurotransmitter pathways and their interactions. Neuroimaging studies identify structural and functional differences in regions such as the frontal cortex and subcortical structures, although findings remain heterogeneous. Genomic research indicates a polygenic basis, with common and rare variants influencing synaptic transmission, neuronal development, regulatory pathways, and related biological processes. These studies also point to shared genetic influences between ADHD and psychological, social, and somatic traits. Additional omics approaches have further expanded these insights, although larger and more integrative studies across multiple layers remain needed. Environmental factors not only influence the onset of ADHD but also shape its course and prognosis, with emerging evidence highlighting complex gene-environment correlations and interactions. Together, the heterogeneity of findings across neuroimaging, genomic, and multi-omics studies underscores the importance of integrative approaches that embrace diversity across populations, methodologies, and biological systems. The present review provides a comprehensive overview of ADHD's biological foundations, highlighting central nervous system mechanisms, their interplay with genetic and environmental factors, and recent advances from multi-omics research with translational potential. We also discuss key methodological considerations, emphasizing that the biological architecture of ADHD is complex, highly polygenic, and spans multiple levels of analysis.<\/jats:p>","DOI":"10.1042\/bsr20254061","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T08:50:24Z","timestamp":1781081424000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A comprehensive overview of the biological foundations of ADHD"],"prefix":"10.1042","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8450-1112","authenticated-orcid":false,"given":"Isabella","family":"Folego-Temoteo","sequence":"first","affiliation":[{"name":"1Laboratory of Physiological Genomics of Mental Health (PhysioGen Lab), Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4719-4397","authenticated-orcid":false,"given":"Yago\u00a0C.","family":"Lima","sequence":"additional","affiliation":[{"name":"1Laboratory of Physiological Genomics of Mental Health (PhysioGen Lab), Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-7126","authenticated-orcid":false,"given":"Eugenio\u00a0H.","family":"Grevet","sequence":"additional","affiliation":[{"name":"2ADHD Outpatient Program & Developmental Psychiatry Program, Hospital de Cl\u00ednicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"},{"name":"3Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Psiquiatria e Medicina Legal, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Psiquiatria e Ci\u00eancias do Comportamento, Porto Alegre, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4469-4257","authenticated-orcid":false,"given":"Marcos\u00a0V.","family":"Vidor","sequence":"additional","affiliation":[{"name":"1Laboratory of Physiological Genomics of Mental Health (PhysioGen Lab), Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2594-066X","authenticated-orcid":false,"given":"Maria\u00a0Eduarda","family":"de A. Tavares","sequence":"additional","affiliation":[{"name":"1Laboratory of Physiological Genomics of Mental Health (PhysioGen Lab), Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-4638","authenticated-orcid":false,"given":"Bruna\u00a0S.","family":"da Silva","sequence":"additional","affiliation":[{"name":"4Universidade Federal de Ci\u00eancias da Sa\u00fade, Departamento de Gen\u00e9tica, Porto Alegre, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-3845","authenticated-orcid":false,"given":"Claiton\u00a0H.D.","family":"Bau","sequence":"additional","affiliation":[{"name":"2ADHD Outpatient Program & Developmental Psychiatry Program, Hospital de Cl\u00ednicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil"},{"name":"3Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Psiquiatria e Medicina Legal, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Psiquiatria e Ci\u00eancias do Comportamento, Porto Alegre, RS, Brazil"},{"name":"5Universidade Federal do Rio Grande do Sul, Instituto de Bioci\u00eancias, Departamento de Gen\u00e9tica, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Gen\u00e9tica e Biologia Molecular, Porto Alegre, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-4927","authenticated-orcid":false,"given":"Diego\u00a0L.","family":"Rovaris","sequence":"additional","affiliation":[{"name":"1Laboratory of Physiological Genomics of Mental Health (PhysioGen Lab), Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"2026061901514586500_B1","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1016\/S0140-6736(24)00757-8","article-title":"Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021","volume":"403","author":"Ferrari","year":"2024","journal-title":"Lancet North Am. 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