M3 - GENE-GENE INTERACTION BETWEEN COMT AND NET IN MODULATING ADHD BEHAVIORS

Abstract

Background Cortico-subcortical circuit dysfunction plays an important role in the manifestation of ADHD symptoms. Dopamine (DA) and Norepinephrine (NE) are major players in the fine regulation of these circuits. Both of these neurotransmitters are major players in maintaining alertness, increasing focus, sustaining thoughts, and facilitating many cognitive functions. Thus, perturbation of either NE, DA (or both) signaling could be implicated in the pathogenesis of ADHD. Hypothesis: Given the dynamic nature of the brain neuromodulation, where any action on one system may reverberate in the other systems, we hypothesize that NE transporter gene could interact with a gene that is essential for the metabolism of DA (COMT Val108/158Met) on modulating ADHD behaviors. Methods 481 children with ADHD (9–12 years old) were included in a 2-week double blind placebo controlled study with methylphenidate. Teachers and parents were asked to evaluate the child's behavior at baseline, placebo, and MPH weeks. Repeated measure ANOVA with between-subject factor of both genes and within-subject factor of experimental conditions (EC) was used. Results A highly significant 3-way interaction (NET⁎COMT⁎EC) was revealed in three SNPs of the NET gene (rs41154 p= 0.002, rs187714 p= 0.001, and rs2242447 p= 0.006) according to the parents’ evaluation. By stratifying the children according to their COMT genotypes, we observe that all children behave in a similar fashion at baseline but respond differently to placebo and MPH. In the Met/Met and Val/Val genotype groups, children who are carrying the AG genotype of rs41154, CT genotype of rs41154, and CT genotype of rs41154 tend to respond poorly compared to patients with the GG, CC, and CT genotypes respectively on placebo and MPH. Discussion Taken together, the current results suggest the epistatic interaction between COMT and NET genetic polymorphisms on response to pharmacological probes. Suggesting that complex gene-by-gene interactions may be important.