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 that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met 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 Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population.
Highlights
Down syndrome (DS) is an aneuploidy syndrome that is most commonly caused by trisomy for human chromosome 21 (HSA21) leading to a cognitive and behavioral phenotype characterized by psychomotor delay, cognitive and behavioral deficits, and high risk for early onset of Alzheimer Disease (AD)-like dementia (Grieco et al, 2015)
Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to prefrontal cortex (PFC)-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population
Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here examined the association between DA related polymorphisms VNTR-DAT1 and COMTVal158Met and interindividual differences in executive function, adaptive behavior and early symptoms of dementia in DS young adults
Summary
Down syndrome (DS) is an aneuploidy syndrome that is most commonly caused by trisomy for human chromosome 21 (HSA21) leading to a cognitive and behavioral phenotype characterized by psychomotor delay, cognitive and behavioral deficits, and high risk for early onset of Alzheimer Disease (AD)-like dementia (Grieco et al, 2015). Executive function and adaptive behavior are impaired in DS adults, with the majority of studies showing specific deficits in working memory, attention, mental flexibility, and inhibitory control (Edgin et al, 2012) These functions are commonly ascribed to the prefrontal cortex (PFC) and frontostriatal networks. The DAT1 polymorphism is a VNTR (variable number tandem repeat) of 40 nucleotides that can range from three to eleven repetitions and has been shown to affect expression of DAT, with the 10-repeat allele being associated with lower DAT levels than the 9-repeat allele (van de Giessen et al, 2009; Shumay et al, 2011) Both the Met allelic variant and 10-repeat allele would result in greater availability of DA in the PFC, which may be linked to better PFC-dependent cognitive skills (Meyer-Lindenberg et al, 2005; Wonodi et al, 2009; Barnett et al, 2011), whereas these same alleles had been associated with a disadvantage in adaptive behavior (Mier et al, 2009; Koutsilieri et al, 2014)
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