Serotonin system genes and childhood-onset aggression.

Twin and adoption studies suggest that childhood aggressive and disruptive behaviour is highly heritable and that continuity in aggressive behaviour is largely mediated by genetic factors (Van Beijsterveldt et al., 2003). To date, few studies have examined the role of serotonin system genes in the pathogenesis of childhoodonset aggression (COA). The sample for the present study has been previously described (Beitchman et al., 2006). The participants were 78 (67 boys and 11 girls; 80% Caucasian, 20% African ancestry) psychiatricallyreferred children (mean age 9.4 years; SD 2.5 years) with scores at or above the 90th percentile on the Aggression subscales of both the parent-reported Child Behaviour Checklist (mean t score 80 ± 10) and the teacherreported Teacher’s Report Form (mean t score 78 ± 10) (Achenbach and Rescorla, 2001), and a 2-year parentreported history of aggressive behaviour. Diagnostic and statistical manual of mental disorder-IV (American Psychiatric Association, 1994) diagnoses for disruptive behaviour disorders were obtained through administration of the Diagnostic Interview Schedule for Children (DISC) to the participant’s primary caretaker and reviews of the participants’ health records. All cases qualified for at least one disruptive behaviour disorder and 57 for attentiondeficit/hyperactive disorder (ADHD). We performed a case–control study to test for associations between polymorphisms of the 5HT1A, 5HT1D, 5HT1B, 5HT2A, and TPH2 genes and persistent, pervasive COA. Ethnically matched adults with no history of psychiatric illness served as controls. We examined a total of 11 loci, all of which were in low to moderate linkage disequilibrium. With the Bonferroni correction, only the 5HT2A Tyr452 allele was significantly associated with clinical status (w = 8.67, d.f. = 1, P = 0.0032). We found 22 (16%) Tyr452 alleles in the cases and seven (5%) in the controls; 116 (84%) His452 alleles in the cases and 131 (95%) in the controls. None of the markers were significantly associated with ADHD. The results indicate that the Tyr452 allele in the 5HT2A receptor is a significant risk factor for COA, but is not associated with comorbid ADHD. The 5HT2A receptor is heavily distributed in the frontal cortex, an area of the brain involved in impulse control. It is therefore interesting to note that the functionally significant (Ozaki et al., 1997) 5HT2A His452Tyr polymorphism appears to confer a susceptibility to aggression that cannot be explained by the presence of comorbid ADHD. Children with a history of extreme, pervasive aggression have a high likelihood of exhibiting antisocial behaviour as adults. Some of our comparison participants may have been aggressive as children, but it is unlikely many (< 10%) would have met the stringent criteria required for the child participants. Importantly, if some of the comparison participants had been aggressive as children, demonstrating differences between cases and controls would be more difficult, making our results more conservative. Despite matching comparison participants on sex and ethnicity, the possibility of population stratification, on the basis of socioeconomic class and ethnicity, still exists. Given the relatively small sample, these results should be considered preliminary and replication of these findings is necessary.