Open AccessTPH2 5′‐ and 3′‐regulatory polymorphisms are differentially associated with HPA axis function and self‐injurious behavior in rhesus monkeys
Author(s) -
Chen G.L.,
Novak M. A.,
Meyer J. S.,
Kelly B. J.,
Vallender E. J.,
Miller G. M.
Publication year - 2010
Publication title -
genes, brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.315
H-Index - 91
eISSN - 1601-183X
pISSN - 1601-1848
DOI - 10.1111/j.1601-183x.2010.00564.x
Subject(s) - tph2 , endocrinology , medicine , biology , haplotype , genotype , allele , allele frequency , polymorphism (computer science) , serotonin , tryptophan hydroxylase , genetics , serotonergic , gene , receptor
Tryptophan hydroxylase‐2 (TPH2) synthesizes neuronal serotonin and is linked to numerous behavioral traits. We have previously characterized the functionality of polymorphisms (especially 2051A>C) in 3’‐untranslated region (3’‐UTR) of rhesus monkey TPH 2 (rh TPH 2). This study further assessed the functionality of additional polymorphisms (–1605T>C, –1491Tn, –1485(AT)n, –1454A>G, –1325In>Del and –363T>G) in rh TPH 2 5’‐flanking region (5’‐FR), and evaluated the effects of rh TPH 2 5’ and 3’ genotypes on central serotonin turnover, hypothalamic–pituitary–adrenal (HPA) axis function and self‐injurious behavior (SIB) in 32 unrelated adult male monkeys of Indian origin. Haplotypes of the rh TPH 2 5’‐FR polymorphisms exert a significant, cell‐dependent effect on reporter gene expression, primarily conferred by –1485(AT)n. The –1485(AT)n and 2051A>C polymorphisms interact to influence cerebrospinal fluid (CSF) 5‐HIAA and plasma adrenocorticotropic hormone (ACTH) in the afternoon. While –1485(AT)n exerts significant main effects on the afternoon cortisol level and nocturnal HPA negative feedback, 2051A>C has significant main effects on the morning cortisol level and cortisol response to ACTH challenge, as well as marginally significant main effects on the daytime HPA negative feedback and self‐biting rate. In addition, the genotype/allele frequency of the 5’‐FR –1325Ins>Del differed significantly between the self‐wounders and non‐wounders, whereas 3’‐UTR 2128S>L polymorphism differed significantly in genotype/allele frequency between the high‐ and low‐frequency biters. This study shows the functionality of rh TPH 2 5’‐FR polymorphisms, and provides evidence for the differential association of rh TPH 2 5’‐FR and 3’‐UTR polymorphisms with HPA axis function and SIB. Our findings shed light on the role of TPH 2 gene variance in physiology and behavioral traits, and also contribute to the understanding of the pathophysiology and genetics of SIB