A common TPH2 haplotype regulates the neural processing of a cognitive control demand.

The monoamine neurotransmitter, serotonin, critically regulates the function of the cerebral cortex and is involved in psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin with the neuron-specific TPH2 isoform present exclusively in the brain and encoded by the TPH2 gene on chromosome 12q21. The haplotype structure of TPH2 was defined for 16 single-nucleotide polymorphisms (SNPs) in a healthy subject population and a haplotype block analysis confirmed the presence of a six SNP haplotype in a yin configuration that has previously been associated with risk for suicidality, depression, and anxiety disorders. Functional magnetic resonance imaging (fMRI) was used to assess the influence of TPH2 variation on brain function related to cognitive control using the Multi-Source Interference Task (MSIT). The MSIT-related blood oxygen level-dependent (BOLD) response was increased with increasing copies of the TPH2 yin haplotype for the dorsal anterior cingulate cortex (dACC), right inferior frontal cortex (IFC), and anterior striatum. A functional connectivity analysis further revealed that increasing numbers of the TPH2 yin haplotype was associated with diminished functional coupling between the dACC and the right IFC, precentral gyrus, parietal cortex and dlPFC. A moderation analysis indicated that the relationship between neural processing networks and cognitive control was significantly modulated by allelic variation for the TPH2 yin haplotype. These findings suggest that the association of risk for psychiatric disorders with a common TPH2 yin haplotype is related to the inefficient functional engagement of cortical areas involved in cognitive control and alterations in the mode of functional connectivity of dACC pathways.

The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density.

BACKGROUND: A 40-bp variable number of tandem repeats (VNTR) polymorphism exists in the 15th exon of DAT1, the gene encoding the human dopamine transporter (DAT). Though the VNTR resides in a region encoding the 3' untranslated region (UTR) and does not alter the protein's amino acid sequence, the prevalent 10-repeat variant has shown both linkage and association to Attention Deficit Hyperactivity Disorder (ADHD). In this study, we examined the effects of the DAT1 VNTR on measures of in vitro DAT expression and pharmacology. A series of four DAT1 constructs, each containing the DAT1 coding region, but varying with respect to the downstream presence or content of the 3'UTR, were engineered and stably transfected into an HEK-293 variant using Flp-In integration, an enzyme-mediated, site-specific recombination technology. RESULTS: [3H] Win 35,428 saturation binding assays and DAT immunoblots revealed statistically significant differences in DAT expression attributable to DAT1 genotype. Cells harboring the 10-repeat DAT1 variant were characterized by a Bmax approximately 50% greater than cells with the 9-repeat VNTR; those containing only the DAT1 coding region or the coding region flanked by a truncated 3' UTR resulted in greater DAT density than either of the naturalistic 9- and 10-repeat variants. Competition binding assays showed no statistically significant DAT1 genotype effects on the DAT affinity for methylphenidate, a finding consistent with the positional location of the VNTR. CONCLUSION: This study identified the DAT1 VNTR as a functional polymorphism and provides an interpretive framework for its association with behavioral phenotypes.