Association between cytochrome P450 2D6 genotype and harm avoidance

Genetic polymorphisms within the serotonergic and dopaminergic neurotransmitter systems may be associated with heightened harm avoidance and novelty seeking. It is also conceivable that polymorphisms in enzymes that mediate the metabolism of endogenous amines within the brain may influence these components of temperament. The CYP2D6 enzyme is expressed at low levels in the brain, and has been shown to mediate the formation of the neurotransmitters serotonin and dopamine from trace amines. Some 5-10% of Caucasians are CYP2D6 deficient due to inactivating mutations in the CYP2D6 gene, and are termed poor metabolizers (PMs). In this study, we investigated whether temperament varied significantly between PMs and CYP2D6 extensive metabolizers (EMs) using the Temperament and Character Inventory (TCI). CYP2D6 genotypes were determined for 121 depressed patients. Of these patients, 113 were inferred from genotype as being EMs and eight as PMs. A significant difference in temperament was observed between inferred CYP2D6 EM and PM individuals. CYP2D6 PMs had significantly lower harm avoidance scores (P = 0.003) than EMs. Furthermore, analysis of the harm avoidance sub-scales revealed that the CYP2D6 PMs scored significantly lower on "fear of uncertainty" (P < 0.001), fatigability (P = 0.009), and shyness (P = 0.038) than EMs, but did not differ significantly from EMs on the worry/pessimism sub-scale. No significant difference in character scores was detected between inferred CYP2D6 EMs and PMs. Our findings suggest that the CYP2D6 polymorphism may impact on personality, and one potential mechanism for this would be by influencing the generation of endogenous neurotransmitters in the brain. (C) 2004 Wiley-Liss, Inc.