COMT Polymorphisms and Anxiety-Related Personality Traits

Abstract

High neuroticism and low extraversion are characteristic of anxiety-prone individuals. A functional variant in the catechol-Omethyltransferase (COMT) gene, the Val158Met ('val/met') polymorphism, has been associated in some prior studies with several phenotypes, including neuroticism. We tested the hypothesis that the val158met polymorphism would be associated with both high neuroticism and low extraversion, making it a plausible candidate locus for anxiety susceptibility. To determine whether val158met is responsible for these effects, we also evaluated the association with haplotypes that included two other SNPs within the COMT gene. We collected a sample of 497 undergraduate college students who were phenotyped on a personality inventory (the NEO-Personality Inventory-Raised (NEO-PI-R)). Subjects were genotyped for three COMT polymorphisms: the well-studied nonsynonymous SNP rs4680 that generates a valine-to-methionine substitution (val158met), rs737865 (near exon #1), and rs165599 (also functional, near the 3 0 -UTR). Together, these three SNPs define a haplotype that is associated with reduced COMT expression in human brain. Logistic regression analyses were used to examine the effects of individual SNPs on extraversion and neuroticism scores. Score tests for association between these traits (quantitatively and dichotomously considered) and haplotypes were also conducted. We evaluated potential for population stratification artifact by genotyping a set of 36 unlinked highly polymorphic markers previously demonstrated to distinguish sufficiently ancestry of major American populations. Two of the SNPs (rs4680 ('val/met') and rs737865) were significantly associated with (low) extraversion and, less consistently, with (high) neuroticism, with effects confined to women. A significant association between COMT haplotype and (low) extraversion and (high) neuroticism was also observed. Formal testing showed that population structure did not explain the findings. These data suggest that involvement of the COMT locus in susceptibility to anxiety-related traits (ie low extraversion and high neuroticism) is unlikely to be wholly accounted for by the well-studied rs4680 ('val/met') polymorphism. Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained.

Association of the Val158Met Catechol O-Methyltransferase Genetic Polymorphism with Panic Disorder

“…Our findings are in line with a recent study on phobic Association of COMT with panic disorder C Rothe et al anxiety that has been reported to be associated with the valine allele of the functional COMT polymorphism in a sample of 1234 women (McGrath et al, 2004). A recent association study of COMT and anxiety-related personality traits described two significant haplotypes which we found in our case-control sample significant as well (Stein et al, 2005). A study by Bray et al (2003) showed that apart from the Val/Met polymorphism, COMT variants are of functional importance.…”

“…An association has been found also in schizophrenia (Goldberg et al, 2003;Shifman et al, 2002), major depression (Massat et al, 2005), rapid cycling in bipolar illness (Kirov et al, 1998) and anxiety-related personality traits (Stein et al, 2005). This might indicate that the involvement of COMT variants would be a 'general deficit' leading to several syndromes rather than to a 'specific deficit' associated to PD or any other particular syndrome.…”

“…Haplotypes have been described to be associated with schizophrenia (Palmatier et al, 2004;Shifman et al, 2002) and seem to have an influence on the susceptibility of anxiety-related personality traits (Stein et al, 2005). Therefore, we investigated, in addition to the Val158Met polymorphism, two markers of the COMT gene chosen in the above mentioned studies that might be associated with PD (Shifman et al, 2002;Stein et al, 2005).…”

“…Recently, three markers of the COMT gene (Figure 1), including the Val158Met variant, were investigated for an association with anxiety-related personality traits in an extensive study of 497 college students (Stein et al, 2005). Two of the SNPs showed an association with low extraversion and high neuroticism, particularly in women.…”

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

“…Of note, several authors found that genetic variants of the COMT gene play a role in personality dimensions in female subjects but not in male subjects (Kim et al, 2006;Stein et al, 2005;Qian et al, 2003;Eley et al, 2003). Interestingly a sexually dimorphic effect of COMT Val158Met alleles was also found in ADHD patients, wherein the Val allele may contribute to ADHD risk in female subjects (Qian et al, 2003).…”