RESEARCH ARTICLE Genetic Variants in the Catechol-o-Methyltransferase Gene Are Associated With Impulsivity and Executive Function: Relevance for Major Depression Dorottya Pap, 1 Xenia Gonda, 2 Eszter Molnar, 1 Judit Lazary, 2 Anita Benko, 1 Darragh Downey, 3 Emma Thomas, 3 Diana Chase, 3 Zoltan G. Toth, 4,5 Krisztina Mekli, 3 Hazel Platt, 6 Antony Payton, 6 Rebecca Elliott, 3 Ian M. Anderson, 3 J.F. William Deakin, 3 Gyorgy Bagdy, 1 and Gabriella Juhasz 1,3 * 1 Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary 2 Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary 3 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 4 Faculty of Life Sciences, The University of Manchester, Manchester, UK 5 Kando Kalman Faculty of Electrical Engineering, Obuda University, Budapest, Hungary 6 Faculty of Medical and Human Sciences, Centre for Integrated Genomic Medical Research, School of Translational Medicine, The University of Manchester, Manchester, UK Manuscript Received: 13 January 2012; Manuscript Accepted: 20 August 2012 The catechol-o-methyltransferase (COMT) gene has been exten- sively 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 popu- lation cohorts: Manchester (n ¼ 1267) and Budapest (n ¼ 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 ¼ 207). Our results demon- strated 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 demon- strated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk 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. Additional supporting information may be found in the online version of this article. 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. Grant sponsor: Sixth Framework Program of the EU NewMood; Grant number: LSHM-CT-2004-503474; Grant sponsor: NIHR Manchester Biomedical Research Centre; Grant number: HRF T03298/2000; Grant sponsor: Hungarian Ministry of Health; Grant numbers: RG 318-041-2009, TAMOP-4.2.1, B-09/1/KMR-2010-0001. *Correspondence to: Dr. Gabriella Juhasz, 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. E-mail: gabriella.juhasz@manchester.ac.uk Article first published online in Wiley Online Library (wileyonlinelibrary.com): 24 September 2012 DOI 10.1002/ajmg.b.32098 Ó 2012 Wiley Periodicals, Inc. 928 Neuropsychiatric Genetics