title: VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome.
abstract: Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase (COMTVal158Met)and the dopamine transporter(VNTR-DAT1). Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found thatVNTR-DAT1was in Hardy-Weinberg equilibrium butCOMTVal158Methad a reduced frequency ofMetallele homozygotes. In our population, genotypes conferring higher DA availability, such asMetallelecarriersand VNTR-DAT110-repeatallele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility.Metallele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities thanValallele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants ofCOMTVal158MetandVNTR-DAT1may contribute to PFC-dependent cognition, while onlyCOMTVal158Metis involved in behavioral phenotypes of DS, similar to euploid population.
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Departament de Farmacologia, de Terapèutica i de Toxicologia, Universidad Autónoma de BarcelonaBarcelona, Spain.
authors: Laura
authors: L
authors: Del Hoyo
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Cellular & Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation, The Barcelona Institute of Science and TechnologyBarcelona, Spain; Department of Experimental and Health Sciences, Universidad Pompeu FabraBarcelona, Spain.
authors: Laura
authors: L
authors: Xicota
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Department of Statistics and Operations Research, Universidad Politècnica de Cataluña/BarcelonaTechBarcelona, Spain.
authors: Klaus
authors: K
authors: Langohr
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute Barcelona, Spain.
authors: Gonzalo
authors: G
authors: Sánchez-Benavides
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Cellular & Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation, The Barcelona Institute of Science and TechnologyBarcelona, Spain.
authors: Susana
authors: S
authors: de Sola
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute Barcelona, Spain.
authors: Aida
authors: A
authors: Cuenca-Royo
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute Barcelona, Spain.
authors: Joan
authors: J
authors: Rodriguez
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Department of Experimental and Health Sciences, Universidad Pompeu FabraBarcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto Salud Carlos IIIMadrid, Spain.
authors: Jose
authors: J
authors: Rodríguez-Morató
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Departament de Farmacologia, de Terapèutica i de Toxicologia, Universidad Autónoma de BarcelonaBarcelona, Spain.
authors: Magí
authors: M
authors: Farré
authors: Cellular & Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation, The Barcelona Institute of Science and TechnologyBarcelona, Spain; Department of Experimental and Health Sciences, Universidad Pompeu FabraBarcelona, Spain; CIBER de Enfermedades Raras, Instituto Salud Carlos IIIMadrid, Spain.
authors: Mara
authors: M
authors: Dierssen
authors: Integrative Pharmacology and Systems Neuroscience Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research InstituteBarcelona, Spain; Department of Experimental and Health Sciences, Universidad Pompeu FabraBarcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto Salud Carlos IIIMadrid, Spain.
authors: Rafael
authors: R
authors: de la Torre
keywords: COMTVal158Met; Down syndrome; PFC-dependent cognition; VNTR-DAT1; dopamine