Advertisement

Catechol-O-methyl Transferase and Expression of Schizophrenia in 73 Adults with 22q11 Deletion Syndrome

  • Anne S. Bassett
    Correspondence
    Address reprint requests to Anne S. Bassett, M.D., F.R.C.P.C., Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario M6J 1H4 Canada
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Oana Caluseriu
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Search for articles by this author
  • Rosanna Weksberg
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Search for articles by this author
  • Donald A. Young
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Division of Clinical and Metabolic Genetics, Hospital for Sick Children, and Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
    Search for articles by this author
  • Eva W.C. Chow
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author

      Background

      Catechol-O-methyl transferase (COMT) is a candidate gene for schizophrenia with a role in dopamine metabolism, particularly in frontal cortex. COMT is within the region commonly deleted in 22q11 deletion syndrome (22q11DS), a syndrome with high prevalence of schizophrenia. We examined the role of COMT in schizophrenia-related expression in 22q11DS.

      Methods

      We genotyped the COMT functional Val158/108Met allele in 73 Caucasian adults with 22q11DS (36 men, 37 women; aged 33.8, SD 10.1 years; 37 Met, 36 Val hemizygosity) blind to clinical data and assessed effects on symptoms and frontal functioning.

      Results

      The lower activity Met allele was not significantly more prevalent than the Val allele in 33 subjects with schizophrenia. Excitement symptoms were more severe, however, and three frontal cognitive tests (theory of mind, Trails B, and olfactory identification), communication, and social functioning measures showed significantly worse performance with Met allele hemizygosity, even after accounting for effects of schizophrenia.

      Conclusions

      The results suggest that hemizygosity of the COMT functional allele exerts an effect on some measures of frontal functioning in 22q11DS. Elevated levels of tonic dopamine activation associated with the COMT Met allele may underlie these aspects of expression. We must look elsewhere for causes of the high prevalence of schizophrenia in 22q11DS, however.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Badner J.A.
        • Gershon E.S.
        Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
        Mol Psychiatry. 2002; 7: 405-411
        • Baker K.
        • Baldeweg T.
        • Sivagnanasundaram S.
        • Scambler P.
        • Skuse D.
        COMT Val(108/158)Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome.
        Biol Psychiatry. 2005; 58: 23-31
        • Bassett A.S.
        • Chow E.W.C.
        22q11 deletion syndrome: A genetic subtype of schizophrenia.
        Biol Psychiatry. 1999; 46: 882-891
        • Bassett A.S.
        • Chow E.W.
        • AbdelMalik P.
        • Gheorghiu M.
        • Husted J.
        • Weksberg R.
        The schizophrenia phenotype in 22q11 deletion syndrome.
        Am J Psychiatry. 2003; 160: 1580-1586
        • Bassett A.S.
        • Chow E.W.C.
        • Husted J.
        • Weksberg R.
        • Caluseriu O.
        • Webb G.D.
        • et al.
        Clinical features of 78 adults with 22q11 deletion syndrome.
        Am J Med Genet A. 2005; 138: 307-313
        • Bassett A.S.
        • Hodgkinson K.
        • Chow E.W.C.
        • Correia S.
        • Scutt L.E.
        • Weksberg R.
        22q11 deletion syndrome in adults with schizophrenia.
        Am J Med Genet. 1998; 81: 328-337
        • Bearden C.E.
        • Jawad A.F.
        • Lynch D.R.
        • Monterossso J.R.
        • Sokol S.
        • McDonald-McGinn D.M.
        • et al.
        Effects of COMT genotype on behavioral symptomatology in the 22q11.2 deletion syndrome.
        Child Neuropsychol. 2005; 11: 109-117
        • Bearden C.E.
        • Jawad A.F.
        • Lynch D.R.
        • Sokol S.
        • Kanes S.J.
        • McDonald-McGinn D.M.
        • et al.
        Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome.
        Am J Psychiatry. 2004; 161: 1700-1702
        • Bilder R.M.
        • Volavka J.
        • Lachman H.M.
        • Grace A.A.
        The catechol-O-methyltransferase polymorphism: Relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes.
        Neuropsychopharmacology. 2004; 29: 1943-1961
        • Chen J.
        • Lipska B.K.
        • Halim N.
        • Ma Q.D.
        • Matsumoto M.
        • Melhem S.
        • et al.
        Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain.
        Am J Hum Genet. 2004; 75: 807-821
        • Chow E.W.
        • Watson M.
        • Young D.A.
        • Bassett A.S.
        Neurocognitive profile in 22q11 deletion syndrome and schizophrenia.
        Schizophr Res. 2006; 87: 270-278
        • Doty R.L.
        • Shaman P.
        • Dann M.
        Development of the University of Pennsylvania Smell Identification Test: A standardized microencapsulated test of olfactory function.
        Physiol Behav. 1984; 32: 489-502
        • Driscoll D.A.
        • Salvin J.
        • Sellinger B.
        • Budarf M.L.
        • McDonald-McGinn D.M.
        • Zackai E.H.
        • et al.
        Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: Implications for genetic counselling and prenatal diagnosis.
        J Med Genet. 1993; 30: 813-817
        • Dunham I.
        • Collins J.
        • Wadey R.
        • Scambler P.
        Possible role for COMT in psychosis associated with velo–cardio–facial syndrome.
        Lancet. 1992; 340: 1361-1362
        • Egan M.F.
        • Goldberg T.E.
        • Kolachana B.
        • Callicott J.H.
        • Mazzanti C.M.
        • Straub R.E.
        • et al.
        Effect of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizophrenia.
        Proc Natl Acad Sci U S A. 2001; 98: 6917-6922
        • Feinstein C.
        • Eliez S.
        • Blasey C.
        • Reiss A.L.
        Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: Usefulness as phenotypic indicators of schizophrenia risk.
        Biol Psychiatry. 2002; 51: 312-318
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Williams J.B.W.
        Structured Clinical Interview for DSM-IV Axis I Disorders—Clinician Version (SCID-CV). American Psychiatric Association, Washington, DC1997
        • Glatt S.J.
        • Faraone S.V.
        • Tsuang M.T.
        Association between a functional catechol-O-methyltransferase gene polymorphism and schizophrenia: Meta-analysis of case–control and family-based studies.
        Am J Psychiatry. 2003; 160: 469-476
        • Goldman-Rakic P.S.
        • Muly 3rd, E.C.
        • Williams G.V.
        D(1) receptors in prefrontal cells and circuits.
        Brain Res Brain Res Rev. 2000; 31: 295-301
        • Gothelf D.
        • Eliez S.
        • Thompson T.
        • Hinard C.
        • Penniman L.
        • Feinstein C.
        • et al.
        COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.
        Nat Neurosci. 2005; 8: 1500-1502
        • Graf W.D.
        • Unis A.S.
        • Yates C.M.
        • Sulzbacher S.
        • Dinulos M.B.
        • Jack R.M.
        • et al.
        Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.
        Neurology. 2001; 57: 410-416
        • Heaton R.K.
        • Chelune G.J.
        • Talley J.
        • Kay G.G.
        • Curtiss G.
        Wisconsin Card Sorting Test manual, revised and expanded. Psychological Assessment Resources, Odessa, FL1993
        • Horowitz A.
        • Shifman S.
        • Rivlin N.
        • Pisante A.
        • Darvasi A.
        A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients.
        Schizophr Res. 2005; 73: 263-267
        • Karayiorgou M.
        • Morris M.A.
        • Morrow B.
        • Shprintzen R.J.
        • Goldberg R.
        • Borrow J.
        • et al.
        Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.
        Proc Natl Acad Sci U S A. 1995; 92: 7612-7616
        • Kay S.R.
        • Fiszbein A.
        • Opler L.A.
        The positive and negative syndrome scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-275
        • Lachman H.M.
        • Papolos D.F.
        • Saito T.
        • Yu Y.M.
        • Szumlanski C.L.
        • Weinshilboum R.M.
        Human catechol-O-methyltransferase pharmacogenetics description of a functional polymorphism and its potential application to neuropsychiatric disorders.
        Pharmacogenetics. 1996; 6: 243-250
        • Lambe E.K.
        • Krimer L.S.
        • Goldman-Rakic P.S.
        Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey.
        J Neurosci. 2000; 20: 8780-8787
        • Lewis C.M.
        • Levinson D.F.
        • Wise L.H.
        • DeLisi L.E.
        • Straub R.E.
        • Hovatta I.
        • et al.
        Genome scan meta-analysis of schizophrenia and bipolar disorder, Part II: Schizophrenia.
        Am J Hum Genet. 2003; 73: 34-48
        • Lindenmayer J.P.
        • Bernstein-Hyman R.
        • Grochowski S.
        • Bark N.
        Psychopathology of schizophrenia: Initial validation of a 5-factor model.
        Psychopathology. 1995; 28: 22-31
        • Maynard T.M.
        • Haskell G.T.
        • Peters A.Z.
        • Sikich L.
        • Liberman J.A.
        • LaMantia A.-S.
        A comprehensive analysis of 22q11 gene expression in the developing and adult brain.
        Proc Natl Acad Sci U S A. 2003; 100: 14433-14438
        • Meyer-Lindenberg A.
        • Kohn P.D.
        • Kolachana B.
        • Kippenhan S.
        • McInerney-Leo A.
        • Nussbaum R.
        • et al.
        Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype.
        Nat Neurosci. 2005; 8: 594-596
        • Moore J.H.
        A global view of epistasis.
        Nat Genet. 2005; 37: 13-14
        • Munafo M.R.
        • Bowes L.
        • Clark T.G.
        • Flint J.
        Lack of association of the COMT (Val(158/108) Met) gene and schizophrenia: A meta-analysis of case–control studies.
        Mol Psychiatry. 2005; 10: 765-770
        • Murphy K.C.
        • Jones L.A.
        • Owen M.J.
        High rates of schizophrenia in adults with velo–cardio–facial syndrome.
        Arch Gen Psychiatry. 1999; 56: 940-945
        • Reitan R.
        • Wolfson D.
        The Halstead–Reitan Neuropsychological Test Battery. Neuropsychology Press, Tuscon, AZ1985
        • Russell T.A.
        An Examination of “Theory of Mind” in people with schizophrenia and related executive tasks. University College, London1996
        • Silverstein A.B.
        Two- and four- subtest short forms of the Wechsler Adult Intelligence Scale—Revised.
        J Consult Clin Psychol. 1982; 50: 415-418
        • Sparrow S.S.
        • Balla D.A.
        • Cicchetti D.V.
        Vineland Adaptive Behaviour Scales. American Guidance Service, Circle Pines, MN1984
        • Spitzer R.L.
        • Williams J.B.W.
        • Gibbon M.
        • First M.B.
        Structured Clinical Interview for DSM-III-R, Patient Edition. American Psychiatric Press, Washington, DC1990
        • Spreen D.
        • Benton A.L.
        Neurosensory Center Comprehensive Examination for Aphasia. Neuropsychology Laboratory, Victoria, Canada1969
        • Strous R.D.
        • Lapidus R.
        • Viglin D.
        • Kotler M.
        • Lachman H.M.
        Analysis of an association between the COMT polymorphism and clinical symptomatology in schizophrenia.
        Neurosci Lett. 2006; 393: 170-173
        • Wechsler D.
        Wechsler Adult Intelligence Scale—Revised. Psychological Corporation, San Antonio, TX1981
        • Wechsler D.
        Wechsler Adult Intelligence Scale. Third Edition. Psychological Corporation, San Antonio, TX1997
        • Wechsler D.
        Wechsler Abbreviated Scale of Intelligence (WASI). Harcourt Brace Jovanovich, San Antonio, TX1999
        • Wiehahn G.J.
        • Bosch G.P.
        • du Preez R.R.
        • Pretorius H.W.
        • Karayiorgou M.
        • Roos J.L.
        Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients.
        Am J Med Genet B Neuropsychiatr Genet. 2004; 129: 20-22