TPH2 polymorphisms across the spectrum of psychiatric morbidity: A systematic review and meta-analysis

Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior – a TPH2 imaging genetics approach

“…Although the neurobiological implications of the TPH2 rs4570625 polymorphism are not fully understood and the T-variant has been associated with increased as well as decreased central serotonergic transmission in limbic-prefrontal circuits (Zhang et al 2004;Lin et al 2007;Scheuch et al 2007;Ottenhof et al 2018; however see Lin et al, 2007 in a Han population), the present findings may reflect that the TPH2 rs6570625 polymorphism, perhaps reflecting individual differences in 5HT neurotransmission, potentially mediate the impact of ELS on experience-dependent neuroplastic changes in thalamic-limbic-prefrontal circuits engaged in aversive learning. We further suggest the notion that this polymorphism may shape a phenotype with an enhanced capability to detect and avoid potentially threatening stimuli and thus potentially facilitating survival in a malevolent environment (Castellà and Pérez 2004).…”

“…In this study, the opposite association between higher ELS and increased brain volumes observed in the TPH2 rs4570625TT homozygotes contrasts with previous reports on a genetic susceptibility for pronounced ELS-associated brain structural deficits. While some studies that combined the low-frequency TPH2 rs4570625 T-carrier groups initially revealed increased psychopathological risk (Gao et al 2012), anxiety-associated traits (Gutknecht et al 2007) and detrimental effects of ELS (Mandelli et al 2012;Forssman et al 2014), accumulating evidence indicates that TT homozygotes differ from both other variants in terms of lower anxiety-related behavior and psychopathological risk (Reuter et al 2007;Lehto et al 2015;Laas et al, 2017;Ottenhof et al 2018). While reduced gray matter volumes in limbicprefrontal regions have been consistently reported in psychiatric disorders characterized by exaggerated anxiety and deficient emotion regulation (van Tol et al 2010;Bora et al 2012;Ahmed-Leitao et al 2016), associations between emotional functioning and limbic-prefrontal volumes in healthy subjects remain less clear, such that elevated anxiety has been associated with both, volumetric increases as well as decreases in this circuitry (e.g.…”

“…Central serotonin biosynthesis is regulated by the rate-limiting enzyme tryptophan hydroxylase (TPH), with the second isoform TPH2 being exclusively expressed in central serotonin neurons (Walther et al 2003;Zhang et al 2004). Individual differences in the TPH2 encoding gene have been linked to variations in both, central serotonergic neurotransmission, including serotonin (5-HT) synthesis rates in limbic and prefrontal regions (Ottenhof et al 2018) and phenotypic variations in traits associated with emotional reactivity and regulation (Herrmann et al 2006;Gutknecht et al 2007;Reuter et al 2007;Canli et al 2008).…”

“…Based on previous findings suggesting that (a) ELS is associated with brain structural and functional changes in limbic-frontal circuits (Teicher et al 2016) and that (b) TPH2 genetic variations, especially the rs4570625 "G" allele, are shown in a recent meta-analysis to be associated with mood disorders, schizophrenia and suicide presumably by regulating brain 5HT levels, albeit with little direct evidence for the functional role of these SNPs (Ottenhof et al 2018) and that modulation of brain serotonin levels is thought to mediate experiencedependent synaptic plasticity in these circuits (Lesch and Waider 2012), we hypothesized (1) that the impact of ELS on the structural and functional organization of limbic-prefrontal circuit varies as a function of genetic differences in serotonergic transmission related to individual differences in the TPH2 rs4570625 polymorphism, and (2) that ELS-associated neuroplastic changes in this circuitry determine variations in anxious avoidant behavior as assessed by trait punishment sensitivity.…”

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

“…In addition, these authors showed that the mRNAs encoding two transcription factors of the Tph2 gene (Sim1 and Pet1) were significantly upregulated by this knee-loading treatment as well [58]. Reduced serotonin or tph2 expression have been linked to depression, schizophrenia and Alzehimer´s dementia associated neurodegeneration [61][62][63], suggesting that restoration of serotonin levels through mild knee-loading may have therapeutic effects for these disorders.…”