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Effects of a functional COMT polymorphism on brain anatomy and cognitive function in adults with velo-cardio-facial syndrome

Published online by Cambridge University Press:  10 May 2007

T. van Amelsvoort ,
J. Zinkstok ,
M. Figee ,
E. Daly ,
R. Morris ,
M. J. Owen ,
K. C. Murphy ,
L. De Haan ,
D. H. Linszen  and
B. Glaser
...Show all authors
T. van Amelsvoort*
Affiliation:
Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands
J. Zinkstok
Affiliation:
Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands
M. Figee
Affiliation:
Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands
E. Daly
Affiliation:
Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK
R. Morris
Affiliation:
Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK
M. J. Owen
Affiliation:
Department of Psychological Medicine, Cardiff University, Cardiff, UK
K. C. Murphy
Affiliation:
Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK
L. De Haan
Affiliation:
Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands
D. H. Linszen
Affiliation:
Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands
B. Glaser
Affiliation:
Department of Psychological Medicine, Cardiff University, Cardiff, UK
D. G. M. Murphy
Affiliation:
Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK
*
*Address for correspondence: T. van Amelsvoort, M.D., Department of Psychiatry, Academic Medical Centre, Tafelbergweg 25, 1105 BC, Amsterdam, The Netherlands. (Email: t.a.vanamelsvoort@amc.uva.nl)
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Abstract

Background

Velo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS.

Method

The COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery.

Results

After corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found.

Conclusions

COMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS.

Keywords

COMTVCFS22q11MRIcognition
Type
Original Articles
Information
Psychological Medicine , Volume 38 , Issue 1 , January 2008 , pp. 89 - 100
Copyright
Copyright © Cambridge University Press 2007

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References

Akil, M, Kolachana, BS, Rothmond, DA, Hyde, TM, Weinberger, DR, Kleinman, JE (2003). Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. Journal of Neuroscience 23, 2008–2013.CrossRefGoogle ScholarPubMed
Andersen, SL, Dumont, NL, Teicher, MH (1997). Developmental differences in dopamine synthesis inhibition by (+/−)-7-OH-DPAT. Naunyn Schmiedebergs Arch Pharmacol 356, 173–181.CrossRefGoogle ScholarPubMed
APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV). American Psychiatric Association: Washington, DC.Google Scholar
Baddeley, AD, Emslie, H, Nimmo-Smith, I (1994). The Doors and People Test: a Test of Visual and Verbal Recall and Recognition. Thames Valley Test Company: Bury St. Edmunds.Google Scholar
Baker, K, Baldeweg, T, Sivagnanasundaram, S, Scambler, P, Skuse, D (2005). COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. Biological Psychiatry 58, 23–31.CrossRefGoogle ScholarPubMed
Baker, SC, Rogers, RD, Owen, AM, Frith, CD, Dolan, RJ, Frackowiak, RS, Robbins, TW (1996). Neural systems engaged by planning: a PET study of the Tower of London task. Neuropsychologia 34, 515–526.CrossRefGoogle ScholarPubMed
Barta, PE, Dhingra, L, Royall, R, Schwartz, E (1997). Improving stereological estimates for the volume of structures identified in three-dimensional arrays of spatial data. Journal of Neuroscience Methods 75, 111–118.CrossRefGoogle ScholarPubMed
Bassett, AS, Caluseriu, O, Weksberg, R, Young, DA, Chow, EW (2007). Catechol-O-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome. Biological Psychiatry. doi: 10.1016/j.biopsych.2006.07.038.CrossRefGoogle ScholarPubMed
Bearden, CE, Jawad, AF, Lynch, DR, Sokol, S, Kanes, SJ, McDonald-McGinn, DM, Saitta, SC, Harris, SE, Moss, E, Wang, PP, Zackai, E, Emanuel, BS, Simon, TJ (2004). Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. American Journal of Psychiatry 161, 1700–1702.CrossRefGoogle ScholarPubMed
Benton, AL, Hamsher, KS (1976). Multilingual Aphasia Examination. University of Iowa: Iowa City, IA.Google Scholar
Brammer, MJ, Bullmore, ET, Simmons, A, Williams, SC, Grasby, PM, Howard, RJ, Woodruff, PW, Rabe-Hesketh, S (1997). Generic brain activation mapping in functional magnetic resonance imaging: a nonparametric approach. Magnetic Resonance Imaging 15, 763–770.CrossRefGoogle ScholarPubMed
Bullmore, E, Brammer, M, Rouleau, G, Everitt, B, Simmons, A, Sharma, T, Frangou, S, Murray, R, Dunn, G (1995). Computerized brain tissue classification of magnetic resonance images: a new approach to the problem of partial volume artifact. Neuroimage 2, 133–147.CrossRefGoogle Scholar
Bullmore, ET, Suckling, J, Overmeyer, S, Rabe-Hesketh, S, Taylor, E, Brammer, MJ (1999). Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. IEEE Transactions on Medical Imaging 18, 32–42.CrossRefGoogle ScholarPubMed
Campbell, LE, Daly, E, Toal, F, Stevens, A, Azuma, R, Catani, M, Ng, V, Van Amelsvoort, T, Chitnis, X, Cutter, W, Murphy, DG, Murphy, KC (2006). Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study. Brain 129, 1218–1228.CrossRefGoogle ScholarPubMed
Chen, J, Lipska, BK, Halim, N, Ma, QD, Matsumoto, M, Melhem, S, Kolachana, BS, Hyde, TM, Herman, MM, Apud, J, Egan, MF, Kleinman, JE, Weinberger, DR (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
Chow, EW, Mikulis, DJ, Zipursky, RB, Scutt, LE, Weksberg, R, Bassett, AS (1999). Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia. Biological Psychiatry 46, 1436–1442.CrossRefGoogle ScholarPubMed
Conner, CK (1995). Continuous Performance Test. Multi-Health Systems Inc.: Toronto, Canada.Google Scholar
Dunham, I, Collins, J, Wadey, R, Scambler, P (1992). Possible role for COMT in psychosis associated with velo-cardio-facial syndrome. Lancet 340 (8831), 1361–1362.CrossRefGoogle ScholarPubMed
Egan, MF, Goldberg, TE, Kolachana, 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
Glaser, B, Debbane, M, Hinard, C, Morris, MA, Dahoun, SP, Antonarakis, SE, Eliez, S (2006). No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome. American Journal of Psychiatry 163, 537–539.CrossRefGoogle ScholarPubMed
Goldstein, KH, Scheerer, M (1941). Abstract and concrete behaviour: an experimental study with special tests. Psychological Monographs 53, no. 2.CrossRefGoogle Scholar
Gothelf, D, Eliez, S, Thompson, T, Hinard, C, Penniman, L, Feinstein, C, Kwon, H, Jin, S, Jo, B, Antonarakis, SE, Morris, MA, Reiss, AL (2005). COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neuroscience 8, 1500–1502.CrossRefGoogle ScholarPubMed
Graf, WD, Unis, AS, Yates, CM, Sulzbacher, S, Dinulos, MB, Jack, RM, Dugaw, KA, Paddock, MN, Parson, WW (2001). Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism. Neurology 57, 410–416.CrossRefGoogle ScholarPubMed
Ho, BC, Wassink, TH, O'Leary, DS, Sheffield, VC, Andreasen, NC (2005). Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Molecular Psychiatry 10, 287–298.CrossRefGoogle ScholarPubMed
Hong, J, Shu-Leong, H, Tao, X, Lap-Ping, Y (1998). Distribution of catechol-O-methyltransferase expression in human central nervous system. Neuroreport 9, 2861–2864.CrossRefGoogle ScholarPubMed
Kates, WR, Antshel, KM, AbdulSabur, N, Colgan, D, Funke, B, Fremont, W, Higgins, AM, Kucherlapati, R, Shprintzen, RJ (2006). A gender-moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo-cardio-facial syndrome (22q11.2 deletion syndrome). American Journal of Medical Genetics, B: Neuropsychiatric Genetics 141, 274–280.CrossRefGoogle Scholar
Kates, WR, Burnette, CP, Jabs, EW, Rutberg, J, Murphy, AM, Grados, M, Geraghty, M, Kaufmann, WE, Pearlson, GD (2001). Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biological Psychiatry 49, 677–684.CrossRefGoogle ScholarPubMed
Lachman, HM, Papolos, DF, Saito, T, Yu, YM, 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
Levy, R, Goldman-Rakic, PS (2000). Segregation of working memory functions within the dorsolateral prefrontal cortex. Experimental Brain Research 133, 23–32.CrossRefGoogle ScholarPubMed
Malhotra, AK, Kestler, LJ, Mazzanti, C, Bates, JA, Goldberg, T, Goldman, D (2002). A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. American Journal of Psychiatry 159, 652–654.CrossRefGoogle ScholarPubMed
McAlonan, GM, Daly, E, Kumari, V, Critchley, HD, Van Amelsvoort, T, Suckling, J, Simmons, A, Sigmundsson, T, Greenwood, K, Russell, A, Schmitz, N, Happe, F, Howlin, P, Murphy, DG (2002). Brain anatomy and sensorimotor gating in Asperger's syndrome. Brain 125, 1594–1606.CrossRefGoogle ScholarPubMed
Meyer-Lindenberg, A, Kohn, PD, Kolachana, B, Kippenhan, S, McInerney-Leo, A, Nussbaum, R, Weinberger, DR, Berman, KF (2005). Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nature Neuroscience 8, 594–596.CrossRefGoogle ScholarPubMed
Mitnick, RJ, Bello, JA, Shprintzen, RJ (1994). Brain anomalies in velo-cardio-facial syndrome. American Journal of Medical Genetics 54, 100–106.CrossRefGoogle ScholarPubMed
Morris, RG, Downes, JJ, Robbins, TW (1990). The nature of the dysexecutive syndrome in Parkinson's disease. In Lines of Thinking (ed. Gilhooly, K.J., Keane, M.T.G., Logie, R.H. and Erdos, G.), pp. 247–258. John Wiley: New York.Google Scholar
Morris, RG, Downes, JJ, Sahakian, BJ, Evenden, JL, Heald, A, Robbins, TW (1988). Planning and spatial working memory in Parkinson's disease. Journal of Neurology, Neurosurgery & Psychiatry 51, 757–766.CrossRefGoogle ScholarPubMed
Murphy, DG, DeCarli, CD, Daly, E, Gillette, JA, McIntosh, AR, Haxby, JV, Teichberg, D, Schapiro, MB, Rapoport, SI, Horwitz, B (1993 b). Volumetric magnetic resonance imaging in men with dementia of the Alzheimer type: correlations with disease severity. Biological Psychiatry 34, 612–621.CrossRefGoogle ScholarPubMed
Murphy, DG, DeCarli, C, Daly, E, Haxby, JV, Allen, G, White, BJ, McIntosh, AR, Powell, CM, Horwitz, B, Rapoport, SI (1993 a). X-chromosome effects on female brain: a magnetic resonance imaging study of Turner's syndrome. Lancet 342, 1197–1200.CrossRefGoogle Scholar
Murphy, DG, DeCarli, C, Schapiro, MB, Rapoport, SI, Horwitz, B (1992). Age-related differences in volumes of subcortical nuclei, brain matter, and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging. Archives of Neurology 49, 839–845.CrossRefGoogle ScholarPubMed
Murphy, KC, Jones, LA, Owen, MJ (1999). High rates of schizophrenia in adults with velo-cardio-facial syndrome. Archives of General Psychiatry 56, 940–945.CrossRefGoogle ScholarPubMed
Nagy, Z, Westerberg, H, Klingberg, T (2004). Maturation of white matter is associated with the development of cognitive functions during childhood. Journal of Cognitive Neurosciences 16, 1227–1233.CrossRefGoogle ScholarPubMed
Nieoullon, A (2002). Dopamine and the regulation of cognition and attention. Progress in Neurobiology 67, 53–83.CrossRefGoogle ScholarPubMed
Papolos, DF, Faedda, GL, Veit, S, Goldberg, R, Morrow, B, Kucherlapati, R, Shprintzen, RJ (1996). Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? American Journal of Psychiatry 153, 1541–1547.Google ScholarPubMed
Parini, A, Coupry, I, Laude, D, Diop, L, Vincent, M, Sassard, J, Dausse, JP (1988). Noradrenaline content and adrenergic receptors in kidney and heart of the prehypertensive and hypertensive Lyon rat strain. American Journal of Hypertension 1, 140–145.CrossRefGoogle ScholarPubMed
Press, WH, Taukolsy, SA, Vetterling, WT, Flannery, BP (1992). Numerical Recipes in C: The Art of Scientific Computing, 2nd edn. Cambridge University Press: Cambridge.Google Scholar
Shallice, T (1982). Specific impairments of planning. Philosophical Transactions of the Royal Society (London) 298, 199–209.Google ScholarPubMed
Shashi, V, Keshavan, MS, Howard, TD, Berry, MN, Basehore, MJ, Lewandowski, E, Kwapil, TR (2006). Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome. Clinical Genetics 69, 234–238.CrossRefGoogle ScholarPubMed
Shprintzen, RJ, Goldberg, RB, Lewin, ML, Sidoti, EJ, Berkman, MD, Argamaso, RV, Young, D (1978). A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate Journal 15, 56–62.Google ScholarPubMed
Sigmundsson, T, Suckling, J, Maier, M, Williams, S, Bullmore, E, Greenwood, K, Fukuda, R, Ron, M, Toone, B (2001). Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. American Journal of Psychiatry 158, 234–243.CrossRefGoogle ScholarPubMed
Simon, TJ, Ding, L, Bish, JP, McDonald-McGinn, DM, Zackai, EH, Gee, J (2005). Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study. Neuroimage 25, 169–180.CrossRefGoogle ScholarPubMed
Smolka, MN, Schumann, G, Wrase, J, Grusser, SM, Flor, H, Mann, K, Braus, DF, Goldman, D, Buchel, C, Heinz, A (2005). Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. Journal of Neuroscience 25, 836–842.CrossRefGoogle ScholarPubMed
Sowell, ER, Thompson, PM, Holmes, CJ, Jernigan, TL, Toga, AW (1999). In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nature Neuroscience 2, 859–861.CrossRefGoogle ScholarPubMed
Suckling, J, Brammer, MJ, Lingford-Hughes, A, Bullmore, ET (1999 a). Removal of extracerebral tissues in dual-echo magnetic resonance images via linear scale-space features. Magnetic Resonance Imaging 17, 247–256.CrossRefGoogle ScholarPubMed
Suckling, J, Sigmundsson, T, Greenwood, K, Bullmore, ET (1999 b). A modified fuzzy clustering algorithm for operator independent brain tissue classification of dual echo MR images. Magnetic Resonance Imaging 17, 1065–1076.CrossRefGoogle ScholarPubMed
Talairach, J, Tournoux, P (1988). Co-Planar Stereotaxic Atlas of the Human Brain. Thieme Medical Publishers: New York.Google Scholar
Tunbridge, EM, Harrison, PJ, Weinberger, DR (2006). Catechol-o-methyltransferase, cognition, and psychosis: Val(158)Met and beyond. Biological Psychiatry 60, 141–151.CrossRefGoogle Scholar
Van Amelsvoort, T, Daly, E, Henry, J, Robertson, D, Ng, V, Owen, M, Murphy, KC, Murphy, DG (2004 a). Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: preliminary results of a structural magnetic resonance imaging study. Archives of General Psychiatry 61, 1085–1096.CrossRefGoogle ScholarPubMed
Van Amelsvoort, T, Daly, E, Robertson, D, Suckling, J, Ng, V, Critchley, H, Owen, MJ, Henry, J, Murphy, KC, Murphy, DG (2001). Structural brain abnormalities associated with deletion at chromosome 22q11: quantitative neuroimaging study of adults with velo-cardio-facial syndrome. British Journal of Psychiatry 178, 412–419.CrossRefGoogle ScholarPubMed
Van Amelsvoort, T, Henry, J, Morris, R, Owen, M, Linszen, D, Murphy, K, Murphy, D (2004 b). Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophrenia Research 70, 223–232.CrossRefGoogle ScholarPubMed
Wahlstrom, D, White, T, Hooper, CJ, Vrshek-Schallhorn, S, Oetting, WS, Brott, MJ, Luciana, M (2007). Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents. Biological Psychiatry 61, 626.CrossRefGoogle ScholarPubMed
Warrington, EK, James, M (1991). The Visual Object and Space Perception Battery. Thames Valley Test Company: Titchfield, UK.Google Scholar
Wechsler, D (1981). The Wechsler Adult Intelligence Scale – Revised. Psychological Corporation: New York.Google Scholar
Wechsler, D (1987). Wechsler Memory Scale – Revised: Manual. The Psychological Corporation: San Antonio, TX.Google Scholar
Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, JE, Giel, R, Jablenski, A, Regier, D, Sartorius, N (1990). SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Archives of General Psychiatry 47, 589–593.CrossRefGoogle ScholarPubMed