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TPH2 5'- and 3'-regulatory polymorphisms are differentially associated with HPA axis function and self-injurious
G-L Chen1, M A Novak, J S Meyer
1Harvard Medical School, New England Primate Research Center, Southborough, MA 01772-9102, USA.
Genes, Brain, and Behavior
|January 12, 2010
Summary
Genetic variations in tryptophan hydroxylase-2 (TPH2) influence serotonin production and are linked to behavior. This study found that TPH2 5'-flanking region and 3'-untranslated region polymorphisms affect the hypothalamic-pituitary-adrenal (HPA) axis and self-injurious behavior (SIB) in rhesus monkeys.
Area of Science:
- Neurogenetics
- Behavioral Genetics
- Primate Molecular Biology
Background:
- Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme for serotonin synthesis in the brain.
- TPH2 gene variants are associated with various behavioral traits and neurological disorders.
- Previous studies characterized rhesus monkey TPH2 (rhTPH2) 3'-untranslated region (3'-UTR) polymorphisms; this study investigates 5'-flanking region (5'-FR) variants.
Purpose of the Study:
- To assess the functionality of novel rhTPH2 5'-FR polymorphisms.
- To evaluate the combined effects of rhTPH2 5'-FR and 3'-UTR genotypes on central serotonin turnover, hypothalamic-pituitary-adrenal (HPA) axis function, and self-injurious behavior (SIB).
- To explore the genetic underpinnings of SIB in rhesus monkeys.
Main Methods:
- Reporter gene assays were used to determine the functional impact of rhTPH2 5'-FR polymorphisms and haplotypes on gene expression.
- Genotyping of 5'-FR and 3'-UTR polymorphisms was performed in 32 unrelated adult male rhesus monkeys.
- Measurements included cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA), plasma adrenocorticotropic hormone (ACTH), cortisol levels, and behavioral assessments of SIB.
Main Results:
- rhTPH2 5'-FR haplotypes significantly influenced reporter gene expression, with the -1485(AT)n polymorphism being a primary driver.
- Interactions between the -1485(AT)n (5'-FR) and 2051A>C (3'-UTR) polymorphisms affected CSF 5-HIAA and plasma ACTH levels.
- Specific 5'-FR and 3'-UTR polymorphisms showed significant associations with HPA axis parameters (cortisol, ACTH, negative feedback) and SIB frequency/severity.
Conclusions:
- rhTPH2 5'-FR polymorphisms possess functional significance, impacting gene expression and physiological traits.
- Differential associations of rhTPH2 5'-FR and 3'-UTR variants with HPA axis function and SIB highlight their complex regulatory roles.
- These findings contribute to understanding the genetic basis of TPH2 function, HPA axis regulation, and the pathophysiology of SIB.
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