AUTHOR=del Hoyo Laura , Xicota Laura , Langohr Klaus , Sánchez-Benavides Gonzalo , de Sola Susana , Cuenca-Royo Aida , Rodriguez Joan , Rodríguez-Morató Jose , Farré Magí , Dierssen Mara , de la Torre Rafael ,  The TESDAD Study Group , Cuenca-Royo Aida , Principe Alessandro , Benejam Bessy , Civit Ester , Hernandez Gimena , Sánchez-Benavides Gonzalo , Bléhaut Henri , Dueñas Iván , Pujol Jesús , Rodríguez Joan , Peña-Casanova Jordi , Espadaler Josep Ma , Sánchez Judit , Trias Katy , Langohr Klaus , Roca Laia , Blanco Laura , del Hoyo Laura , Xicota Laura , Farr Magí , Dierssen Mara , de la Torre Rafael , Freixas Rut , Videla Sebastiá , Catuara-Solarz Silvina , de Sola Susana , Legout Valérie 

TITLE=VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=10

YEAR=2016

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2016.00193

DOI=10.3389/fnbeh.2016.00193

ISSN=1662-5153

ABSTRACT=<p>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 (<italic>COMTVal158Met)</italic> and the dopamine transporter <italic>(VNTR-DAT1)</italic>. 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 that <italic>VNTR-DAT1</italic> was in Hardy-Weinberg equilibrium but <italic>COMTVal158Met</italic> had a reduced frequency of <italic>Met</italic> allele homozygotes. In our population, genotypes conferring higher DA availability, such as <italic>Met</italic> allele <italic>carriers</italic> and VNTR-DAT1 <italic>10-repeat</italic> allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. <italic>Met</italic> allele 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 than <italic>Val</italic> allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of <italic>COMTVal158Met</italic> and <italic>VNTR-DAT1</italic> may contribute to PFC-dependent cognition, while only <italic>COMTVal158Met</italic> is involved in behavioral phenotypes of DS, similar to euploid population.</p>