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.