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Data from epidemiological genetic studies suggest that variability in personality traits is explained, at least partly, by genetic factors. Recently, a growing number of molecular genetic studies have suggested the involvement of the serotonin system in specific traits.To investigate the association between three serotonergic polymorphisms [A-1438G (rs6311) of the HTR2A gene, and STin2 VNTR and 5-HTTLPR of the SLC6A4 gene] and personality traits assessed with the Temperament and Character Inventory.Four hundred and four unrelated healthy volunteers [50% males, mean age (standard deviation)=40.5 (11.3)] from Asturias (northern Spain) were genotyped using standard methods. Cloninger's Temperament and Character Inventory was used for investigation of temperament and character traits.The genetic variants were in Hardy–Weinberg equilibrium and genotypic frequencies were similar in both the sexes. 5-HTTLPR was associated with a direct effect on self directedness (F=6.20, P=0.002), and interacting with educational level (F=3.10, P=0.016) and A-1438G (F=3.34, P=0.011) with respect to novelty seeking. STin2 VNTR interacted with age in relation to reward dependence (F=2.74, P=0.013) and with sex in relation to cooperation (F=5.10, P=0.007). In addition, SLC6A4 haplotypes had significant effects on harm avoidance (lower in volunteers with L12), self directedness (higher in volunteers with L12), and self transcendence (higher in volunteers with S10).Our findings suggest a strong genetic component in personality traits manifested primarily through interaction effects that occur between genetic factors alone and between genetic and demographic factors.