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Effects of two dopamine-modulating genes (DAT1 9/10 and COMT Val/Met) on n-back working memory performance in healthy volunteers

Published online by Cambridge University Press:  19 May 2010

M. M. Blanchard ,
S. R. Chamberlain ,
J. Roiser ,
T. W. Robbins  and
U. Müller
M. M. Blanchard
Affiliation:
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
S. R. Chamberlain
Affiliation:
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
J. Roiser
Affiliation:
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
T. W. Robbins
Affiliation:
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK Department of Experimental Psychology, University of Cambridge, Cambridge, UK
U. Müller*
Affiliation:
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
*
*Address for correspondence: Dr U. Müller, Department of Psychiatry, University of Cambridge, Box 189, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. (Email: um207@cam.ac.uk)
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Abstract

Background

Impairments in working memory are present in many psychiatric illnesses such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia. The dopamine transporter and catechol-O-methyltransferase (COMT) are proteins involved in dopamine clearance and the dopamine system is implicated in the modulation of working memory (WM) processes and neurochemical models of psychiatric diseases. The effects of functional polymorphisms of the dopamine transporter gene (DAT1) and the COMT gene were investigated using a visuospatial and numerical n-back working memory paradigm. Our n-back task was designed to reflect WM alone, and made no demands on higher executive functioning.

Method

A total of 291 healthy volunteers (aged 18–45 years) were genotyped and matched for age, sex, and Barratt Impulsivity Scale (BIS) and National Adult Reading Test (NART) scores. To assess individual gene effects on WM, factorial mixed model analysis of variances (ANOVAs) were conducted with the between-subjects factor as genotype and difficulty level (0-, 1-, 2- and 3-back) entered as the within-subjects factor.

Results

The analysis revealed that the DAT1 or COMT genotype alone or in combination did not predict performance on the n-back task in our sample of healthy volunteers.

Conclusions

Behavioral effects of DAT1 and COMT polymorphisms on WM in healthy volunteers may be non-existent, or too subtle to identify without exceedingly large sample sizes. It is proposed that neuroimaging may provide more powerful means of elucidating the modulatory influences of these polymorphisms.

Keywords

Catechol-O-methyl transferasedopamine transporterprefrontal cortexworking memory
Type
Original Articles
Information
Psychological Medicine , Volume 41 , Issue 3 , March 2011 , pp. 611 - 618
Copyright
Copyright © Cambridge University Press 2010

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References

Barkley, RA (1997). Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychological Bulletin 121, 65–94.CrossRefGoogle ScholarPubMed
Barnett, JH, Jones, PB, Robbins, TW, Müller, U (2007). Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Molecular Psychiatry 12, 502–509.CrossRefGoogle ScholarPubMed
Barnett, JH, Scoriels, L, Munafo, MR (2008). Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biological Psychiatry 64, 137–144.CrossRefGoogle ScholarPubMed
Bertolino, A, Blasi, G, Latorre, V, Rubino, V, Rampino, A, Sinibaldi, L, Caforio, G, Petruzzella, V, Pizzuti, A, Scarabino, T, Nardini, M, Weinberger, DR, Dallapiccola, B (2006). Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. Journal of Neuroscience 26, 3918–3922.CrossRefGoogle ScholarPubMed
Bilder, RM, Volavka, J, Lachman, HM, Grace, AA (2004). The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 29, 1943–1961.CrossRefGoogle Scholar
Bruder, EG, Keilp, JG, Xu, H, Shikhman, M, Schori, E, Gorman, JM, Gilliam, C (2005). Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biological Psychiatry 58, 901–907.CrossRefGoogle ScholarPubMed
Caldu, X, Vendrell, P, Bartres-Faz, D, Clemente, I, Bargallo, N, Jurado, MA, Serra-Grabulosa, JM, Junque, C (2007). Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects. NeuroImage 37, 1437–1444.CrossRefGoogle ScholarPubMed
Castellanos, FX, Tannock, R (2002). Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nature Reviews Neuroscience 3, 617–628.CrossRefGoogle ScholarPubMed
Chamberlain, SR, Del Campo, N, Dowson, J, Müller, U, Clark, L, Robbins, TW, Sahakian, BJ (2007). Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biological Psychiatry 62, 977–984.CrossRefGoogle ScholarPubMed
Chen, J, Lipska, B, Halim, N, Ma, Q, Matsumoto, M, Melhem, S, Kolachana, B, Hyde, T, Herman, M, Apud, J (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics 75, 807–821.CrossRefGoogle ScholarPubMed
Chudasama, Y, Robbins, TW (2006). Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans. Biological Psychology 73, 19–38.CrossRefGoogle ScholarPubMed
Cools, R, Sheridan, M, Jacobs, E, D'Esposito, M (2007). Impulsive personality predicts dopamine-dependent changes in frontostriatal activity during component processes of working memory. Journal of Neuroscience 27, 5506–5514.CrossRefGoogle ScholarPubMed
Crow, TJ (2007). How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. American Journal of Psychiatry 164, 13–21.CrossRefGoogle Scholar
de Frias, CM, Marklund, P, Eriksson, E, Larsson, A, Öman, L, Annerbrink, K, Bäckman, L, Nilsson, LG, Nyberg, L (2010). Influence of COMT gene polymorphism on fMRI-assessed sustained and transient activity during a working memory task. Journal of Cognitive Neuroscience 22, 1614–1622.CrossRefGoogle ScholarPubMed
Demiralp, T, Herrmann, SC, Erdal, ME, Ergenoglu, T, Keskin, YH, Ergen, M, Beydagi, H (2007). DRD4 and DAT1 polymorphisms modulate human gamma band responses. Cerebral Cortex 17, 1007–1019.CrossRefGoogle ScholarPubMed
Egan, MF, Goldberg, TE, Bhaskar, BS, Callicott, JH, Mazzanti, CM, Straub, RE, Goldman, D, Weinberger, DR (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences USA 98, 6917–6922.CrossRefGoogle ScholarPubMed
Ettinger, U, Joober, R, De Guzman, R, O'Driscoll, GA (2006). Schizotypy, attention deficit hyperactivity disorder, and dopamine genes. Psychiatry and Clinical Neurosciences 60, 764–767.CrossRefGoogle ScholarPubMed
Faraone, SV, Perlis, RH, Doyle, AE, Smoller, JW, Goralnick, JJ, Holmgren, MA, Sklar, P (2005). Molecular genetics of attention-deficit/hyperactivity disorder. Biological Psychiatry 57, 1313–1323.CrossRefGoogle ScholarPubMed
Flint, J, Munafo, MR (2007). The endophenotype concept in psychiatric genetics. Psychological Medicine 37, 163–180.CrossRefGoogle ScholarPubMed
Goldberg, TE, Egan, MF, Gscheidle, T, Coppola, R, Weickert, T, Kolachana, BS, Goldman, D, Weinberger, DR (2003). Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Archives of General Psychiatry 60, 889–896.CrossRefGoogle ScholarPubMed
Goldman-Rakic, PS (1994). The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biological Psychiatry 46, 650–661.CrossRefGoogle Scholar
Gottesman, II, Gould, TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645.CrossRefGoogle ScholarPubMed
Gray, CM, Konig, P, Engel, AK, Singer, W (1989). Oscillatory response in the cat visual cortex exhibit intercolumnar synchronization which reflects global stimulus properties. Nature 338, 334–337.CrossRefGoogle ScholarPubMed
Hazy, TE, Frank, MJ, O'Reilly, RC (2006). Banishing the homunculus: making working memory work. Neuroscience 139, 105–118.CrossRefGoogle ScholarPubMed
Heinz, A, Goldman, D, Jones, DW, Palmour, R, Hommer, D, Gorey, JG, Lee, KS, Linnoila, M, Weinberger, DR (2000). Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22, 133–139.CrossRefGoogle ScholarPubMed
Howard, MW, Rizzuto, DS, Caplan, JB, Madsen, JR, Lisman, J, Aschenbrenner-Scheibe, R, Schulze-Bonhage, A, Kahana, MJ (2003). Gamma oscillations correlate with working memory load in humans. Cerebral Cortex 13, 1369–1374.CrossRefGoogle ScholarPubMed
Lachman, HM, Papolos, DF, Saito, T, Yu, YW, Szumlanski, CL, Weinshilboum, RM (1996). Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6, 243–250.CrossRefGoogle ScholarPubMed
Levinson, DF (2006). The genetics of depression: a review. Biological Psychiatry 60, 84–92.CrossRefGoogle ScholarPubMed
Lewis, DA, Melchitzky, DS, Sesack, SR, Whitehead, RE, Auh, S, Sampson, A (2001). Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. Journal of Comprehensive Neurology 432, 119–136.CrossRefGoogle ScholarPubMed
Lopez-Leon, S, Janssens, AC, Gonzalez-Zuloeta Ladd, AM, Del-Favero, J, Claes, SJ, Oostra, BA, van Duijn, CM (2007). Meta-analyses of genetic studies on major depressive disorder. Molecular Psychiatry 13, 772–785.CrossRefGoogle ScholarPubMed
Lutzenberger, W, Ripper, B, Busse, L, Birbaumer, N, Kaiser, J (2002). Dynamics of gamma-band activity during an audiospatial working memory task in humans. Journal of Neuroscience 22, 5630–5638.CrossRefGoogle ScholarPubMed
Lynch, DR, Mozley, PD, Sokol, S, Maas, NM, Balcer, LJ, Siderowf, AD (2003). Lack of effect of polymorphisms in dopamine metabolism related genes on imaging of TRODAT-1 in striatum of asymptomatic volunteers and patients with Parkinson's disease. Movement Disorders 18, 804–812.CrossRefGoogle ScholarPubMed
Meyer-Lindenberg, A, Weinberger, DR (2006). Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nature Reviews Neuroscience 7, 818–827.CrossRefGoogle ScholarPubMed
Nelson, HE, Willison, J (1991). National Adult Reading Test (NART) – Test Manual, 2nd edn. NFER-Nelson: Windsor, Berks.Google Scholar
Patton, JH, Stanford, MS, Barratt, ES (1995). Factor structure of the Barratt Impulsiveness Scale. Journal of Clinical Psychology 51, 768–774.3.0.CO;2-1>CrossRefGoogle ScholarPubMed
Riley, BP, McGuffin, P (2000). Linkage and associated studies of schizophrenia. American Journal of Medical Genetics 97, 23–44.3.0.CO;2-K>CrossRefGoogle ScholarPubMed
Risch, N (1990). Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genetic Epidemiology 7, 3–16; discussion 17–45.CrossRefGoogle ScholarPubMed
Schott, BH, Seidenbecher, CI, Fenker, DB, Lauer, CJ, Bunzeck, N, Bernstein, HG, Tischmeyer, W, Gundelfinger, ED, Heinze, HJ, Duzel, E (2006). The dopaminergic midbrain participates in human episodic memory formation: evidence from genetic imaging. Journal of Neuroscience 26, 1407–1417.CrossRefGoogle ScholarPubMed
Sesack, SR, Hawrylak, VA, Matus, C, Guido, MA, Levey, AI (1998). Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. Journal of Neuroscience 18, 2697–2708.CrossRefGoogle ScholarPubMed
Stefanis, NC, Van Os, J, Avramopoulos, D, Smyrnis, N, Evdokimidis, I, Hantoumi, I (2004). Variation in catechol-O-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men. Biological Psychiatry 56, 510–515.CrossRefGoogle Scholar
Taylor Tavares, JV, Clark, L, Cannon, DM, Erickson, K, Drevets, WC, Sahakian, BJ (2007). Distinct profiles of neurocognitive function in unmedicated unipolar depression and bipolar II depression. Biological Psychiatry 62, 917–924.CrossRefGoogle ScholarPubMed
van Dyck, CH, Malison, RT, Jacobsen, LK, Seibyl, JP, Staley, JK, Laruelle, M, Baldwin, RM, Innis, RB, Gelernter, J (2005). Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. Journal of Nuclear Medicine 46, 745–751.Google ScholarPubMed
Vandenbergh, DJ, Persico, AM, Hawkins, AL, Griffin, CA, Li, X, Jabs, EW, Uhl, GR (1992 a). Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14, 1104–1106.CrossRefGoogle ScholarPubMed
Vandenbergh, DJ, Persico, AM, Uhl, GR (1992 b). A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs. Brain Research. Molecular Brain Research 15, 161–166.CrossRefGoogle Scholar
VanNess, SH, Owens, MJ, Kilts, CD (2005). The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genetics 6, 55.CrossRefGoogle ScholarPubMed
Waldman, ID (2005). Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biological Psychiatry 57, 1347–1356.CrossRefGoogle ScholarPubMed