Gender-Dependent Association of the Functional Catechol-O-Methyltransferase Val158Met Genotype with Sensation Seeking Personality Trait

Abstract

The gene encoding cathechol-O-methyltransferase (COMT) contains a common functional missense polymorphism (Val158Met) that regulates dopamine in an allele-dependent manner. A pivotal role of dopamine neurotransmission in the prefrontal cortex has been implicated in drug-seeking behavior and related personality traits, such as sensation seeking, with some evidence for a gender-specific association. Here, we tested the hypothesis that the COMT Val158Met polymorphism modulates the personality dimension, sensation seeking, in a gender-dependent manner. Study sample included 214 male (age 38.1712.6 years) and 218 female (age 36.1713.6 years) healthy volunteers, who were assessed with Zuckerman's sensation-seeking scale and genotyped for the Val158Met polymorphism (dbSNP:rs4680). Univariate analysis of variance showed that the sensation seeking score was significantly affected by a COMT genotype  gender interaction (F ¼ 5.330, df ¼ 2, p ¼ 0.005). The Val158Met polymorphism was associated with the sensation seeking personality trait in women only. The highest scores in the sensation-seeking scale and in three of the four subscales were observed in female subjects with the Val/Val genotype relative to women carrying the Met allele. Our results suggest that high COMT enzyme activity associated with the Val allele predisposes to high sensation seeking scores in female subjects and add to increasing evidence for a gender specific role of COMT in normal and dysfunctional behavior.

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…A sex-by-genotype interaction (po0.0005) was seen by Lang et al (2007) who showed that the Val 158 allele was associated with the personality trait of sensation-seeking in women. This finding is the latest in a line of studies that show relationships between COMT genotype and personality traits in women but not in men.…”

“…The studies vary in the robustness and plausibility of the finding with regard to sex, in several respects. Few have been statistically convincing, eg by demonstrating a sex-by-genotype interaction (eg Kates et al, 2006;Lang et al, 2007). Many studies simply found an association that reached significance in one sex but not in the other, without demonstrating an interaction between sex and genotype (eg Enoch et al, 2006), an approach further compromised by the fact that the nonsignificant sex often had a smaller sample size and less power than did the significant one (eg Nolan et al, 2000;Ono et al, 2004;Stein et al, 2005).…”

Sex Modulates the Associations Between the COMT Gene and Personality Traits

“…Sex differences in COMT activity and in personality are well addressed in the literature (Carver and White, 1994;Cloninger et al, 2006;Darcan et al, 2008;Harrison and Tunbridge, 2008;Schmitt et al, 2008). In fact, several studies (Eley et al, 2003;Enoch et al, 2003;Reuter et al, 2006b;Lang et al, 2007) have reported sex-dependent COMT effects on personality, although others (Strobel et al, 2003;Reuter and Hennig 2005;Hoth et al, 2006;Hashimoto et al, 2007;Wacker and Gatt, 2010) reported no interactions between sex and the COMT gene.…”

“…Traits such as harm avoidance (HA) in TCI, neuroticism in NEO, and BIS all belong to negative emotionality (NEM), whereas novelty seeking (NS) in TCI, extraversion in NEO, and BAS belong to positive emotionality (PEM; Reuter et al, 2006b). Associations between COMT Val/Met and PEM/NEM were quite mixed, with nine studies showing no significant associations (Strobel et al, 2003;Tochigi et al, 2006;Ishii et al, 2007;Light et al, 2007;Urata et al, 2007;Sheldrick et al, 2008;Calati et al, 2011;Kang et al, 2010;Salo et al, 2010), seven studies showing the Val allele associated with high PEM or low NEM (Enoch et al, 2003;Tsai et al, 2004;Reuter and Hennig, 2005;Stein et al, 2005;Hoth et al, 2006;Hashimoto et al, 2007;Wacker and Gatt, 2010), and three studies showing the opposite (Met allele associated with high PEM or low NEM; Kim et al, 2006;Golimbet et al, 2007;Demetrovics et al, 2010), and three studies reported opposite pattern for males and females (Eley et al, 2003;Reuter et al, 2006b;Lang et al, 2007).…”

“…This amino acid substitution influences the thermal stability and activity of COMT, such that the COMT activity in human prefrontal cortex is about 35-50% lower in Met homozygotes than in Val homozygotes . As a result, dopamine signaling is likely to be enhanced in Met carriers as compared with Val carriers, thus resulting in potential differences in prefrontal cognitive function Barnett et al, 2008;Goldman et al, 2009) and personality (Benjamin et al, 2000;Eley et al, 2003;Enoch et al, 2003;Tsai et al, 2004;Olsson et al, 2005;Reuter and Hennig, 2005;Stein et al, 2005;Kim et al, 2006;Reuter et al, 2006a;Tochigi et al, 2006;Golimbet et al, 2007;Hashimoto et al, 2007;Ishii et al, 2007;Lang et al, 2007;Light et al, 2007).…”