Oades, R.D., Lasky-Su, J., Christiansen, H., Faraone, S. V., Sonuga-Barke, E. J. S., Banaschewski, T., Chen, W., Anney, R. J. L., Buitelaar, J. K., Ebstein, R. P., Franke, B., Gill, M., Miranda, A., Rothenberger, A., Sergeant, J. A., Steinhausen, H-C., Taylor, E.A., Thompson, M. & Asherson, P.

The influence of serotonin and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behavioral and Brain Functions, 4, 48. Open Access
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Introduction: Low serotonin (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. -- Both types of impulsivity are associated with ADHD, & genes of functional significance for the 5-HT system are implicated in this disorder. -- Here we demonstrate the separation of aggressive & cognitive components of impulsivity from symptom ratings & test their association with 5HT genes using a family-based association test (FBAT-PC). .

Methods: The sample consisted of 1160 offspring from 590 families from the IMAGE study. Impulsive symptoms were assessed using the long forms of the Conners & the SDQ parent & teacher questionnaires. Factor analysis showed the symptoms aggregated into parent- & teacher-rated behavioral & cognitive impulsivity. We then selected 582 SNPs from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs & the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.

1 - In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance.

2 - Nominal significance was also shown for cognitive impulsivity with 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, & TPH2 genes replicating reported associations with ADHD.

3 - For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, & TPH2 genes that have also been reported to be associated with ADHD.

4 - Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) & aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.

5 - a) for both forms of impulsivity PNMT was over - expressed HT1E was over-expressed in the cognitive & under-expressed in the behavioral or aggressive form of impulsivity. b) For cognitive impulsivity 4 SNPs for receptors (apart from HTR1E) were under-expressed in a recessive model (HT2A, HT3B), whereas the availability of 5HT (TPH2 in a dominant model) was influenced by over-expression of relevant alleles. c) For the DA system, nominally significant markers were found for both types of impulsivity, but while the emphasis for the behavioral/aggressive form was on DRD4 (one SNP, in particular the 3-repeat allele, was over-expressed), cognitive impulsivity was nominally associated with uptake (DAT1: 1 SNP) & the D1 receptor (DRD1: 2 SNPs), which were all under-expressed. -- Based on their anatomical distributions, this could reflect top-down m-c & bottom-up m-l mechanisms of control, respectively

Discussion: a) A genetic influence on MA involvement in impulsivity shown by children with ADHD was found. b) There were trends for separate & overlapping influences on impulsive-aggressive behavior & cognitive impulsivity, where an association with PNMT (& arousal mechanisms affected by its activity) was more clearly involved in the latter. c) 5-HT & DA mechanisms were implicated in both forms of impulsivity with a wider range of 5-HT mechanisms (each with a small effect) potentially influencing cognitive impulsivity. d) 5-HT: a number of markers pointed to small effects on synthesis (TPH2 3 SNPs), pre-& post-synaptic receptors (HTR1E, HTR2A, HTR3B: 5 SNPs) & reuptake (SERT: STin2) for cognitive (not behavioral) impulsivitye)

Thus, in aggressive behavioral impulsivity a DRD4 SNP was overexpressed while those for HTR1E & TPH were underexpressed. In contrast in cognitive impulsivity SNPs for DRD1 & DAT1 were underexpressed while others for TPH2 and HTR1E were overexpressed.

These preliminary results should be followed up with an examination of environmental influences & associations with performance on tests of impulsivity in the laboratory.