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.
Article first published online: 24 SEP 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 159B, Issue 8, pages 928–940, December 2012
How to Cite
Pap, D., Gonda, X., Molnar, E., Lazary, J., Benko, A., Downey, D., Thomas, E., Chase, D., Toth, Z. G., Mekli, K., Platt, H., Payton, A., Elliott, R., Anderson, I. M., Deakin, J.F. W., Bagdy, G. and 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., 159B: 928–940. doi: 10.1002/ajmg.b.32098
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.
- Issue published online: 8 NOV 2012
- Article first published online: 24 SEP 2012
- Manuscript Accepted: 20 AUG 2012
- Manuscript Received: 13 JAN 2012
- Sixth Framework Program of the EU NewMood. Grant Number: LSHM-CT-2004-503474
- NIHR Manchester Biomedical Research Centre. Grant Number: HRF T03298/2000
- Hungarian Ministry of Health. Grant Numbers: RG 318-041-2009, TAMOP-4.2.1, B-09/1/KMR-2010-0001
- intermediate phenotype;
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.