Catechol O-methyl transferase and dopamine D2 receptor gene polymorphisms: evidence of positive heterosis and gene–gene interaction on working memory functioning

The COMT Val108/158Met polymorphism has been extensively studied in relation to individual differences in working memory (WM) performance. The present study tested the association of the COMT Val108/158Met polymorphism with WM performance in two independent family-based Dutch samples: 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). A significant association was found between the COMT polymorphism and WM scores in the combined adult and young cohorts. The association reflected positive heterosis such that the Met/Met and Val/Val homozygotes did not perform as well as the Met/Val heterozygotes on the WM tasks. A secondary analysis was conducted in which a DRD2-tagging SNP (rs2075654) was tested for an interactive effect with the COMT polymorphism on WM performance. A significant interactive effect of the DRD2 and COMT genes was found such that heterosis was present only in the DRD2 genotype that has been linked to lower receptor density. Our results support previous findings that WM performance needs an optimal level of dopamine signaling within the PFC. This optimum level depends on enzymatic activity controlling dopamine level as well as dopamine receptor sensitivity, both of which may differ as a function of age and genotype. We conclude that the effects of a single polymorphism in a dopaminergic gene on a well-defined cognitive trait may easily remain hidden if the interaction with age and other genes in the pathway are not taken into account.

[1]  D. Comings,et al.  Reward deficiency syndrome: genetic aspects of behavioral disorders. , 2000, Progress in brain research.

[2]  Martin Reuter,et al.  Association of the functional catechol-O-methyltransferase VAL158MET polymorphism with the personality trait of extraversion , 2005, Neuroreport.

[3]  G. Abecasis,et al.  A general test of association for quantitative traits in nuclear families. , 2000, American journal of human genetics.

[4]  Kenneth K Kidd,et al.  Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles , 1999, Biological Psychiatry.

[5]  G. Williams,et al.  Under the curve: Critical issues for elucidating D1 receptor function in working memory , 2006, Neuroscience.

[6]  B. Emanuel,et al.  Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2. , 1992, Genomics.

[7]  Patrick C. Kyllonen,et al.  Working memory is (almost) perfectly predicted by g , 2004 .

[8]  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.

[9]  Danielle Posthuma,et al.  A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. , 2005, American journal of human genetics.

[10]  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.

[11]  I. Deary,et al.  The functional COMT polymorphism, Val158Met, is associated with logical memory and the personality trait intellect/imagination in a cohort of healthy 79 year olds , 2005, Neuroscience Letters.

[12]  Mark R. Raymond,et al.  Wechsler Intelligence Scale for Children — Revised (WISC-R) Patterns of Strengths and Weaknesses as Predictors of the Intelligence-Achievement Relationship , 1981 .

[13]  Danielle Posthuma,et al.  Netherlands Twin Register: From Twins to Twin Families , 2006, Twin Research and Human Genetics.

[14]  Danielle Posthuma,et al.  A longitudinal twin study on IQ, executive functioning, and attention problems during childhood and early adolescence. , 2006, Acta neurologica Belgica.

[15]  M. Nelen,et al.  Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. , 1993, Science.

[16]  A. Grace,et al.  The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes , 2004, Neuropsychopharmacology.

[17]  E K Perry,et al.  D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. , 1997, Pharmacogenetics.

[18]  Dorret I. Boomsma,et al.  The phenotypic and genotypic relation between working memory speed and capacity , 2006 .

[19]  C. Curtis,et al.  Persistent activity in the prefrontal cortex during working memory , 2003, Trends in Cognitive Sciences.

[20]  C. Gottfries.  Neurochemical aspects on aging and diseases with cognitive impairment , 1990, Journal of neuroscience research.

[21]  D. Boomsma,et al.  High-yield noninvasive human genomic DNA isolation method for genetic studies in geographically dispersed families and populations. , 1995, American journal of human genetics.

[22]  G. Montgomery,et al.  Genetics of Dizygotic Twinning: A Feasibility Study for a Biobank , 2004, Twin Research.

[23]  D. Posthuma,et al.  Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families , 2006, Genes, Brain and Behavior.

[24]  M. D’Esposito,et al.  Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation , 2005, Cognitive, affective & behavioral neuroscience.

[25]  N. Laird,et al.  Family-based designs in the age of large-scale gene-association studies , 2006, Nature Reviews Genetics.

[26]  P. Cowen,et al.  Tyrosine depletion attenuates dopamine function in healthy volunteers , 2001, Psychopharmacology.

[27]  S. Tsai,et al.  Dopamine D2 Receptor and N-Methyl-D-Aspartate Receptor 2B Subunit Genetic Variants and Intelligence , 2002, Neuropsychobiology.

[28]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[29]  J. Fuster.  Network memory , 1997, Trends in Neurosciences.

[30]  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.

[31]  T. Kiviluoto,et al.  Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. , 1994, European Journal of Biochemistry.

[32]  D I Boomsma,et al.  Combined Linkage and Association Tests in Mx , 2004, Behavior genetics.

[33]  Daniel R. Weinberger,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[34]  J O Rinne,et al.  The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers , 1998, Molecular Psychiatry.

[35]  N. Volkow,et al.  Dopamine transporters decrease with age. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[36]  R. Weinshilboum,et al.  Human liver catechol‐O‐methyltransferase pharmacogenetics , 1990, Clinical pharmacology and therapeutics.

[37]  J. Savitz,et al.  The molecular genetics of cognition: dopamine, COMT and BDNF , 2006, Genes, brain, and behavior.

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

[39]  J. J. Ryan,et al.  Wechsler Adult Intelligence Scale-III , 2001 .

[40]  K. Suzuki,et al.  Age-related changes in human D1 dopamine receptors measured by positron emission tomography , 2005, Psychopharmacology.

[41]  D. Posthuma,et al.  The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts , 2006, Molecular Psychiatry.

[42]  M. Egan,et al.  Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  David J. Therriault,et al.  A latent variable analysis of working memory capacity, short-term memory capacity, processing speed, and general fluid intelligence , 2002 .

[44]  J.-J. Lee,et al.  Changes In Endogenous Monoamines In Aged Rats , 2001, Clinical and experimental pharmacology & physiology.

[45]  J K Hewitt,et al.  Combined linkage and association sib-pair analysis for quantitative traits. , 1999, American journal of human genetics.

[46]  J. Axelrod.  O-methylation of epinephrine and other catechols in vitro and in vivo. , 1957 .

[47]  T. Robbins,et al.  Chemistry of the adaptive mind , 2004, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[48]  M. Daly,et al.  Genome-wide association studies for common diseases and complex traits , 2005, Nature Reviews Genetics.

[49]  D. Boomsma,et al.  RESPONSE INTERFERENCE AND WORKING MEMORY IN 12-YEAR-OLD CHILDREN , 2005, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[50]  C. Stefanis,et al.  Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: A population study in 543 young men , 2004, Biological Psychiatry.

[51]  M. Folstein,et al.  EFFECTS OF AGE ON DOPAMINE AND SEROTONIN RECEPTORS MEASURED BY POSITRON TOMOGRAPHY IN THE LIVING HUMAN BRAIN , 1984, Science.

[52]  D. Weinberger,et al.  Genes, dopamine and cortical signal-to-noise ratio in schizophrenia , 2004, Trends in Neurosciences.

[53]  J. Rinne,et al.  Functional imaging studies of dopamine system and cognition in normal aging and Parkinson's disease , 2002, Neuroscience & Biobehavioral Reviews.

[54]  B. Lipska,et al.  Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function , 2003, Neuroscience.