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Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome

  • Author Footnotes
    1 Authors DG and AJL contributed equally to the work.
    Doron Gothelf
    Footnotes
    1 Authors DG and AJL contributed equally to the work.
    Affiliations
    Behavioral Neurogenetics Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Author Footnotes
    1 Authors DG and AJL contributed equally to the work.
    Amanda J. Law
    Footnotes
    1 Authors DG and AJL contributed equally to the work.
    Affiliations
    Departments of Psychiatry and Cell and Developmental Biology, School of Medicine, University of Colorado, Aurora, Colorado

    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Amos Frisch
    Affiliations
    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    The Felsenstein Medical Research Center, Petah Tiqwa, Israel
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  • Jingshan Chen
    Affiliations
    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Omer Zarchi
    Affiliations
    Behavioral Neurogenetics Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Elena Michaelovsky
    Affiliations
    The Felsenstein Medical Research Center, Petah Tiqwa, Israel
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  • Renee Ren-Patterson
    Affiliations
    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Barbara K. Lipska
    Affiliations
    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Miri Carmel
    Affiliations
    The Felsenstein Medical Research Center, Petah Tiqwa, Israel
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  • Bhaskar Kolachana
    Affiliations
    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Abraham Weizman
    Affiliations
    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    The Felsenstein Medical Research Center, Petah Tiqwa, Israel
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  • Daniel R. Weinberger
    Correspondence
    Address correspondence to Daniel R. Weinberger, M.D., Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, 855 Wolfe Street, Baltimore, MD 21205
    Affiliations
    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

    Lieber Institute for Brain Development, Johns Hopkins University Medical Campus

    Departments of Psychiatry, Neurology, and Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Author Footnotes
    1 Authors DG and AJL contributed equally to the work.

      Background

      22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS.

      Methods

      Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m)RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing.

      Results

      There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3′ untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3′ untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 “T” mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals.

      Conclusions

      Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone.

      Key Words

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      Linked Article

      • Catechol-O-Methyltransferase and Genetic Variation Under Hemizygosity
        Biological PsychiatryVol. 75Issue 5
        • Preview
          Less than a decade after Julius Axelrod initially described catechol-O-methyltransferase (COMT) (1), an enzyme he had isolated from rat liver to elaborate epinephrine metabolism, Angelo DiGeorge first hinted at a congenital clinical syndrome of hypoparathyroidism and absence of the thymus (2). There is no reason to suspect that these contemporaries, ensconced in entirely different fields and approaches, would have made particular note of each other’s work, much less anticipated that their respective discoveries might inextricably converge half a century later in the modern era of psychiatric genetics.
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