Journal of the International Neuropsychological Society

Research Articles

COMT Val158Met Genotype and Individual Differences in Executive Function in Healthy Adults

Heather A. Wisharta1 c1, Robert M. Rotha1, Andrew J. Saykina2, C. Harker Rhodesa3, Gregory J. Tsongalisa3, Kristine A. Pattina4, Jason H. Moorea4 and Thomas W. McAllistera1

a1 Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire

a2 Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana

a3 Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire

a4 Department of Genetics, Dartmouth Medical School, Lebanon, New Hampshire


The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and ankyrin repeat and kinase domain containing 1 (ANKK1) genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene–gene interactions that influence central dopaminergic systems. (JINS, 2011, 17, 1–7)

(Received November 06 2009)

(Revised October 18 2010)

(Accepted October 18 2010)

(Online publication December 10 2010)


c1 Correspondence and reprint requests to: Heather A. Wishart, PhD, Neuropsychology Program and Brain Imaging Lab, Department of Psychiatry, Dartmouth Medical School/DHMC, One Medical Center Drive, Lebanon, NH 03756-0001. E-mail: