Gene-environment interactions in the development of combined type ADHD: evidence for a synapse-based model.

To determine the mechanism of interaction of prenatal smoking exposure and child genotype in the development of attention deficit/hyperactivity disorder (ADHD), polymorphisms in the CHRNA4 gene were tested for interactions with prenatal smoking exposure on risk for ADHD subtypes using multiple logistic regression. An exon 5 polymorphism demonstrated a significant interaction with history of maternal smoking during pregnancy for increasing risk for severe combined type ADHD (OR = 3.0, 95% CI 1.1-8.4 for population-defined severe combined type, OR = 3.9 95% CI 1.2-13.1 for DSM-IV defined combined subtype ADHD). This interaction increased the effects of previously reported interactions for the DRD4 and DAT1 genes with prenatal smoking exposure. Given the known functions and the known areas of expression of these three genes at the dopaminergic synapse in the pre-frontal cortex, the results are compatible with a synapse-based model of the development of this form of ADHD. The subtype specificity of these findings supports the concept that ADHD is composed of a group of distinct disorders.