High neuroticism and low extraversion are characteristic of anxiety-prone individuals. A functional variant in the catechol-O-methyltransferase (COMT) gene, the VaI158Met ('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′-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.
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