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Genetic variants in the catechol-o-methyltransferase gene are associated with impulsivity and executive function: Relevance for major depression

Authors

  • Dorottya Pap,

    1. Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
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  • Xenia Gonda,

    1. Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary
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  • Eszter Molnar,

    1. Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
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  • Judit Lazary,

    1. Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary
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  • Anita Benko,

    1. Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
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  • Darragh Downey,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • Emma Thomas,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • Diana Chase,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • Zoltan G. Toth,

    1. Faculty of Life Sciences, The University of Manchester, Manchester, UK
    2. Kando Kalman Faculty of Electrical Engineering, Obuda University, Budapest, Hungary
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  • Krisztina Mekli,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • Hazel Platt,

    1. Faculty of Medical and Human Sciences, Centre for Integrated Genomic Medical Research, School of Translational Medicine, The University of Manchester, Manchester, UK
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  • Antony Payton,

    1. Faculty of Medical and Human Sciences, Centre for Integrated Genomic Medical Research, School of Translational Medicine, The University of Manchester, Manchester, UK
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  • Rebecca Elliott,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • Ian M. Anderson,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • J.F. William Deakin,

    1. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
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  • Gyorgy Bagdy,

    1. Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
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  • Gabriella Juhasz

    Corresponding author
    1. Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
    2. Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, UK
    • Faculty of Medical and Human Sciences, Neuroscience and Psychiatry Unit, School of Community Based Medicine, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
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  • Financial Disclosures: Prof Deakin has carried out consultancy and speaking engagements for Bristol Myers Squibb, AstraZeneca, Eli Lilly, Schering Plough, Janssen-Cilag, and Servier. All fees are paid to the University of Manchester to reimburse them for the time taken. He has share options in P1vital. Prof Anderson has received grant support from AstraZeneca and Servier, consultancy fees/honoraria for speaking/support to attend conferences from Wyeth, Servier, Eli Lilly, Lundbeck, Cephalon and Bristol Myers Squibb. Dr. Elliott has received consultancy fees from Cambridge Cognition and P1Vital. Prof Bagdy, Drs Thomas, Downey, Chase, Payton, Mekli, Gonda, Lazary and Juhasz, Ms Pap, Ms Platt, and Mr Toth report no relevant financial interest.

  • How to Cite this Article: Pap D, Gonda X, Molnar E, Lazary J, Benko A, Downey D, Thomas E, Chase D, Toth ZG, Mekli K, Platt H, Payton A, Elliott R, Anderson IM, Deakin JFW, Bagdy G, Juhasz G. 2012. Genetic Variants in The Catechol-o-Methyltransferase Gene Are Associated With Impulsivity and Executive Function: Relevance for Major Depression. Am J Med Genet Part B 159B:928–940.

Abstract

The catechol-o-methyltransferase (COMT) gene has been extensively investigated in depression with somewhat contradictory results but the role of impulsivity, as a possible intermediate phenotype in this disorder, has not been considered yet. In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in two independent population cohorts: Manchester (n = 1267) and Budapest (n = 942). First, we investigated the association between COMT genotypes, impulsivity, neuroticism and depression using haplotype trend regression, and constructed a model using structural equation modeling to investigate the interaction between these factors. Secondly, we tested the effect of executive function on this model in a smaller interviewed sample (n = 207). Our results demonstrated that COMT haplotypes were significantly associated with impulsivity in the combined cohort, showing the same direction of effects in both populations. The COMT effect on depressive symptoms (in subjects without history of depression) and on executive function (interviewed sample) showed the opposite pattern to impulsivity. Structural equation models demonstrated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk of depression. In addition, better executive function also operated as a risk factor for depression, possibly though reduced ability to flexibly disengage negative emotions. In conclusion, variations in the COMT gene exert complex effects on susceptibility to depression involving various intermediate phenotypes, such as impulsivity and executive function. These findings emphasise that modeling of disease pathways at phenotypic level are valuable for identifying genetic risk factors. © 2012 Wiley Periodicals, Inc.

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