Functional genetic polymorphisms in serotonin and dopamine gene systems and their significance in behavioural disorders.

Many genes in the monoamine neurotransmitter pathways possess functional variants which have been associated with human behavioural disorders and traits, making them of important clinical relevance. In this chapter, we summarize the most recent literature concerning functional studies on these variants and their possible behavioural consequences. Such studies have adopted a variety of strategies. Key investigations have determined effects on gene expression at the level of transcription in mammalian cell cultures, human lymphoblasts and/or human post-mortem brain tissue employing a range of strategies including allele-specific expression. This has enabled the comparison of in vitro and in vivo data, and furthermore provides an improved perceptive of their respective advantages. Pharmacological studies have focused on the effects of gene variation at the protein level in terms of binding to ligands and drugs. Additionally, molecular biological approaches have identified transcription factors (DNA-binding proteins) that interact with the motifs within the polymorphisms themselves. Various neuroimaging studies have further determined the relationship of genotype with protein availability in the brain, thereby contributing further to an understanding of the in vivo functional significance of gene variants. Finally, there is growing evidence from both human and animal studies on the interaction of functional polymorphisms with the environment in determining behavioural outcomes. Taken together, these findings have contributed to a greater understanding of the plausible molecular mechanisms underpinning the functional significance of polymorphisms in monoamine neurotransmitter pathway genes and how they may influence behavioural phenotypes.