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Mutations in sphingolipid metabolism genes are associated with ADHD.
Henriquez-Henriquez, Marcela; Acosta, Maria T; Martinez, Ariel F; Vélez, Jorge I; Lopera, Francisco; Pineda, David; Palacio, Juan D; Quiroga, Teresa; Worgall, Tilla S; Deckelbaum, Richard J; Mastronardi, Claudio; Molina, Brooke S G; Arcos-Burgos, Mauricio; Muenke, Maximilian.
Afiliação
  • Henriquez-Henriquez M; Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • Acosta MT; ELSA Clinical Laboratories (IntegraMedica, part of Bupa), Santiago de Chile, Chile.
  • Martinez AF; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Vélez JI; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Lopera F; Universidad del Norte, Barranquilla, Colombia.
  • Pineda D; Neuroscience Research Group, University of Antioquia, Medellin, Colombia.
  • Palacio JD; Neuroscience Research Group, University of Antioquia, Medellin, Colombia.
  • Quiroga T; Neuroscience Research Group, University of Antioquia, Medellin, Colombia.
  • Worgall TS; Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • Deckelbaum RJ; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
  • Mastronardi C; Department of Pediatrics, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • Molina BSG; Neuroscience Group (NeurUROS), Institute of Translational Medicine, School of Medicine and Health Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.
  • Muenke M; Grupo de Investigación en Psiquiatría (GIPSI), Departamento de Psiquiatría, Instituto de Investigaciones Me´dicas, Facultad de Medicina, Universidad de Antioquia, Medelli´n, Colombia. mauricio.arcos@udea.edu.co.
Transl Psychiatry ; 10(1): 231, 2020 07 13.
Article em En | MEDLINE | ID: mdl-32661301
Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75-80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtorno do Deficit de Atenção com Hiperatividade Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Child / Humans Idioma: En Revista: Transl Psychiatry Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Chile País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtorno do Deficit de Atenção com Hiperatividade Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Child / Humans Idioma: En Revista: Transl Psychiatry Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Chile País de publicação: Estados Unidos