Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects

Two limiting factors of dopamine activity are the catechol-o-methyltransferase (COMT) and the dopamine transporter (DAT), which terminate dopamine activity by degradation and uptake, respectively. Genetic variants of COMT and DAT have been related to the enzymatic activity and protein availability, respectively. The Met allele of the COMT Val108/158 Met polymorphism has been associated to lower enzymatic activity and the 9-repeat allele of the DAT 40 base-pair (bp) variable number of tandem repeat (VNTR) polymorphism has been related to lower protein availability. Genotypes for COMT and DAT were determined in a sample of 75 healthy subjects, who underwent functional magnetic resonance imaging (fMRI) while performing an N-back task. To further assess the effects of the genotypes on cognition, subjects were administered the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test (CPT). Analysis of fMRI data revealed an additive effect of these two genes on brain activation in an N-back task, with subjects homozygous for the Val and the 9-repeat alleles showing the highest activation for the same level of performance. Moreover, the Val allele was related to higher number of perseverative errors on the WCST and with a higher number of commission errors on the CPT. The 10-repeat allele was associated with faster reaction times but also with a higher number of commission errors. Our results support a role of the COMT Val108/158 Met and the DAT 40 bp VNTR in both brain activation and cognition.

[1]  Anthony M. Kang,et al.  Global variation of a 40-bp VNTR in the 3′-untranslated region of the dopamine transporter gene (SLC6A3) , 1999, Biological Psychiatry.

[2]  J. Swanson,et al.  Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample , 2005, Molecular Psychiatry.

[3]  E. Mulvey,et al.  Clinical considerations in the prediction of dangerousness in mental patients , 1984 .

[4]  M. Egan,et al.  Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. , 2004, American journal of human genetics.

[5]  M. D’Esposito,et al.  Functional connectivity during working memory maintenance , 2004, Cognitive, affective & behavioral neuroscience.

[6]  Darin D Dougherty,et al.  Dopamine transporter density in patients with attention deficit hyperactivity disorder , 1999, The Lancet.

[7]  Christian la Fougere,et al.  The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder , 2003, Neuroscience & Biobehavioral Reviews.

[8]  Yu-Shin Ding,et al.  Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain , 2001, The Journal of Neuroscience.

[9]  M. Reuter,et al.  The influence of the dopaminergic system on cognitive functioning: A molecular genetic approach , 2005, Behavioural Brain Research.

[10]  Lars-Göran Nilsson,et al.  Catechol O-Methyltransferase Val158Met Polymorphism is Associated with Cognitive Performance in Nondemented Adults , 2005, Journal of Cognitive Neuroscience.

[11]  R. Coppola,et al.  Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. , 1999, Cerebral cortex.

[12]  Martin Reuter,et al.  Molecular genetics support Gray's personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. , 2007, The international journal of neuropsychopharmacology.

[13]  G. Deuschl,et al.  Patients with Parkinson's disease learn to control complex systems—an indication for intact implicit cognitive skill learning , 2006, Neuropsychologia.

[14]  M. Egan,et al.  Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. , 2003, The American journal of psychiatry.

[15]  Marc Laruelle,et al.  Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  I. Waldman,et al.  Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. , 1998, American journal of human genetics.

[17]  L. Fañanás,et al.  New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. , 2004, The American journal of psychiatry.

[18]  H. Heinze,et al.  The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging , 2006, The Journal of Neuroscience.

[19]  Christian Rosenmund,et al.  Identification of Differentiation-Associated Brain-Specific Phosphate Transporter as a Second Vesicular Glutamate Transporter (VGLUT2) , 2001, The Journal of Neuroscience.

[20]  A. Feingold.  The validity of the information and vocabulary subtests of the WAIS , 1982 .

[21]  Adrian Angold,et al.  Relations Between Continuous Performance Test Performance Measures and ADHD Behaviors , 2003, Journal of abnormal child psychology.

[22]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[23]  Jonathan D. Cohen,et al.  Cognition and control in schizophrenia: a computational model of dopamine and prefrontal function , 1999, Biological Psychiatry.

[24]  Marc Laruelle,et al.  The Variable Number of Tandem Repeats Polymorphism of the Dopamine Transporter Gene Is Not Associated with Significant Change in Dopamine Transporter Phenotype in Humans , 2001, Neuropsychopharmacology.

[25]  A. Tröster,et al.  Utility of a Wisconsin Card Sorting Test short form in persons with Alzheimer's and Parkinson's disease. , 1996, Journal of clinical and experimental neuropsychology.

[26]  M. Delong,et al.  Functional and pathophysiological models of the basal ganglia , 1996, Current Opinion in Neurobiology.

[27]  X Li,et al.  Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. , 1992, Genomics.

[28]  Eric R. Kandel,et al.  DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability , 2007, Schizophrenia Research.

[29]  Douglas W. Jones,et al.  Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum , 2000, Neuropsychopharmacology.

[30]  E H Cook,et al.  Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations , 2000, Molecular Psychiatry.

[31]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

[32]  S. Faraone,et al.  Attention-deficit hyperactivity disorder , 2005, The Lancet.

[33]  N C Andreasen,et al.  Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow , 2005, Molecular Psychiatry.

[34]  I. Kondo,et al.  A 40-nucleotide repeat polymorphism in the human dopamine transporter gene , 1993, Human Genetics.

[35]  P. Buckley,et al.  Catechol-O-Methyltransferase (COMT) Genotypes and Working Memory: Associations with Differing Cognitive Operations , 2007 .

[36]  P. Nathan,et al.  Molecular Imaging of the Dopaminergic System and its Association with Human Cognitive Function , 2006, Biological Psychiatry.

[37]  S. Fuke,et al.  The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression , 2001, The Pharmacogenomics Journal.

[38]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Clinton D Kilts,et al.  The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density , 2005, BMC Genetics.

[40]  B. Madras,et al.  The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD) , 2002, Behavioural Brain Research.

[41]  N J Cox,et al.  Association of attention-deficit disorder and the dopamine transporter gene. , 1995, American journal of human genetics.

[42]  M. Petrides,et al.  Wisconsin Card Sorting Revisited: Distinct Neural Circuits Participating in Different Stages of the Task Identified by Event-Related Functional Magnetic Resonance Imaging , 2001, The Journal of Neuroscience.

[43]  M. Lezak,et al.  Neuropsychological assessment, 4th ed. , 2004 .

[44]  Tommaso Scarabino,et al.  Additive Effects of Genetic Variation in Dopamine Regulating Genes on Working Memory Cortical Activity in Human Brain , 2006, The Journal of Neuroscience.

[45]  B. Madras,et al.  The Dopamine Transporter and Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[46]  C. Kieling,et al.  Association between DRD4 Gene and Performance of Children with ADHD in a Test of Sustained Attention , 2006, Biological Psychiatry.

[47]  T. Ohmori,et al.  Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia , 2007, Journal of Neural Transmission.

[48]  R. Weinshilboum,et al.  Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. , 1999, Annual review of pharmacology and toxicology.

[49]  T. Robbins,et al.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies , 2006, Clinical psychology review.

[50]  M. Gill,et al.  Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism , 1997, Molecular Psychiatry.

[51]  A. Malhotra,et al.  A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. , 2002, The American journal of psychiatry.

[52]  Gereon R. Fink,et al.  Using fMRI to decompose the neural processes underlying the Wisconsin Card Sorting Test , 2006, NeuroImage.

[53]  T. Goldberg,et al.  Dopaminergic modulation of cortical function in patients with Parkinson's disease , 2002, Annals of neurology.

[54]  I. Craig,et al.  Expression of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from brain and lymphocytes using quantitative RT-PCR. , 2002, American journal of medical genetics.

[55]  C. Benkelfat,et al.  Catechol-O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin Card Sorting Test. , 2002, Archives of general psychiatry.