Association of COMT Val158Met genotype with executive functioning following traumatic brain injury.

Catechol-O-methyltransferase (COMT) is thought to functionally modulate dopamine neurons, thus likely influencing frontal-executive functioning. High enzyme activity (COMT Val) and low enzyme activity (COMT Met) are functional polymorphisms resulting from a G to A transition in exon 4 (codon 158) of the human COMT gene. Decreased cortical dopamine should result in poorer executive functioning. Therefore, the authors hypothesized that individuals with traumatic brain injury (TBI) and the low enzyme activity polymorphism would perform better on tests of executive functioning than individuals with the high enzyme activity polymorphism. One hundred thirteen individuals referred to the Defense and Veterans Brain Injury Center underwent a comprehensive TBI evaluation and were genotyped for the COMT polymorphism. Comparison of mean differences among the COMT genotype groups for several measures of aspects of executive functioning was conducted using analysis of variance (ANOVA) with adjustment for multiple comparisons. Homozygotes for the higher activity allele made more perseverative responses on the Wisconsin Card Sorting Test, while homozygotes for the lower activity allele had the least number of perseverative responses. While it cannot be determined whether TBI influenced the association of COMT Val158Met to executive functioning, these data extend the known relationship of genotype to executive performance seen in healthy comparison subjects and individuals with schizophrenia to individuals with TBI.

[1]  D. Warden,et al.  Functional assessment of executive abilities following traumatic brain injury , 2003, Brain injury.

[2]  Bita Moghaddam,et al.  Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders , 2002, Biological Psychiatry.

[3]  M. Lezak.  Neuropsychological assessment, 3rd ed. , 1995 .

[4]  K. Cicerone,et al.  Definition of mild traumatic brain injury , 1993 .

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

[6]  G. Winterer,et al.  Genetics of human prefrontal function , 2003, Brain Research Reviews.

[7]  Sharon K. McDowell,et al.  Differential effect of a dopaminergic agonist on prefrontal function in traumatic brain injury patients. , 1998, Brain : a journal of neurology.

[8]  K. Kidd,et al.  Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation , 2002, Human Genetics.

[9]  J. Sludden,et al.  Ethnic differences in catechol O-methyltransferase pharmacogenetics: frequency of the codon 108/158 low activity allele is lower in Kenyan than Caucasian or South-west Asian individuals. , 1998, Pharmacogenetics.

[10]  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.

[11]  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.

[12]  E. Pehek,et al.  Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat , 2002, Brain Research.

[13]  J. Ecklund,et al.  Cognitive Rehabilitation for Traumatic Brain Injury , 2000 .

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

[15]  A. Sampson,et al.  Dopamine transporter immunoreactivity in monkey cerebral cortex: Regional, laminar, and ultrastructural localization , 2001, The Journal of comparative neurology.

[16]  Christie Golden,et al.  Stroop Color and Word Test: Manual for Clinical and Experimental Uses. , 1978 .

[17]  Robert K. Heaton,et al.  Wisconsin Card Sorting Test Manual – Revised and Expanded , 1993 .

[18]  G. Meco,et al.  Cognitive improvement during Tolcapone treatment in Parkinson's disease , 1997, Journal of Neural Transmission.

[19]  R. Vanderploeg,et al.  APOE genotype influences acquisition and recall following traumatic brain injury , 2002, Neurology.