Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive–compulsive disorder

Abstract

Dysfunction of the central serotonergic system has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The genetic contribution to the development of OCD is particularly high in early-onset OCD. The aim of this study was to investigate the effect of polymorphic variants in the gene of the novel brain-specific tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in OCD with disease onset in childhood and adolescence. We analysed two common single nucleotide polymorphisms (SNPs) of TPH2 in the putative transcriptional control region and in intron 2 of the TPH2 gene in a unique family-based sample of OCD patients with onset of the disease in childhood and adolescence comprising 71 complete, independent trios. The transmission disequilibrium test was used to determine transmission of alleles and haplotypes from parents to offspring. In this first study of TPH2 in OCD, analysis of the SNPs, rs4570625 and rs4565946, revealed a significant preferential transmission of haplotype G-C to children and adolescents with OCD. Moreover, a trend towards preferential transmission of the C allele of SNP rs4565946 to the patients was found. The genotype relative-risk estimate for homozygous C allele carriers of SNP rs4565946 was 2.58 (95% CI 0.98-6.82). In conclusion, the results link TPH2 variations to the pathogenesis of early-onset OCD and further support the aetiological relevance of 5-HT signalling in OCD.

Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons

“…23 Since the discovery of the TPH2 gene in 2003, 4 14 published studies have examined possible associations between TPH2 SNPs and various mental disorders including major depression, 17,24,25 bipolar disorder, 26 anxiety disorders, 27,28 attention-deficit/ hyperactivity disorder (ADHD), 29,30 autism 31 or suicidal behavior. 17,[32][33][34][35][36] The results of these studies have been mixed, with nine studies showing weak, but statistically significant associations between one or more TPH2 SNP and a specific mental disorder, 17,[24][25][26][27][29][30][31][32] and five showing no significant associations. 28,[33][34][35][36] Most of the studies reporting negative results failed to detect statistically significant associations for SNPs in the putative promoter region or intronic SNPs in the 5 0 -end of the gene.…”

“…Mossner et al 27 described an association between obsessive-compulsive disorder (OCD) and the G-C haplotype for rs4570625 and rs4565946, SNPs located in the putative regulatory region and intron 2, respectively. Walitza et al 29 described a weak association between regulatory region SNPs (rs4570625 and rs11178997) and attention-deficit hyperactivity disorder (ADHD).…”

Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice

“…5,6 TPH1 mRNA is expressed in the CNS at extremely low levels, 7 although TPH1 mRNA is robustly expressed in the pineal gland, where TPH mediates melatonin biosynthesis. 5,8 Recent data have suggested a possible association between TPH2 polymorphisms and a variety of psychiatric disorders including major depression, 9-14 suicide, 13,14 attentiondeficit/hyperactivity disorder, [15][16][17] autism, 18 bipolar disorder, 19 and obsessive compulsive disorder. 16 In addition, it has recently been shown that polymorphisms in the 3 0 -UTR of rhesus monkey TPH2 modulate hypothalamic-pituitary-adrenal (HPA) axis function presumably through changes in TPH2 expression.…”

“…5,8 Recent data have suggested a possible association between TPH2 polymorphisms and a variety of psychiatric disorders including major depression, 9-14 suicide, 13,14 attentiondeficit/hyperactivity disorder, [15][16][17] autism, 18 bipolar disorder, 19 and obsessive compulsive disorder. 16 In addition, it has recently been shown that polymorphisms in the 3 0 -UTR of rhesus monkey TPH2 modulate hypothalamic-pituitary-adrenal (HPA) axis function presumably through changes in TPH2 expression. 20 These data suggest that changes in the expression and/or function of TPH2 may be associated with psychiatric disease and emphasize the need to understand what makes TPH isoforms distinct with regard to function and regulation.…”

A loss-of-function mutation in tryptophan hydroxylase 2 segregating with attention-deficit/hyperactivity disorder

“…Variants in the TPH2 sequence have been associated with a spectrum of psychiatric diagnoses, such as obsessive compulsive disorder, affective disorders and attention-deficit/hyperactivity disorder (ADHD). [1][2][3][4][5][6] It has been proposed that naturally occurring variants of TPH2 with decreased enzyme activity could cause deficiency of serotonin production and an increased risk of developing affective disorders. 3 However, all the TPH2 variants described so far are either situated in non-coding regions or are missense mutations with significant residual activity.…”