Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P ¼ 0.049; rs11178997, P ¼ 0.034), but not for the third SNP in intron 2 (rs4565946, P ¼ 0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P ¼ 0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes. Keywords: ADHD; serotonin; TPH2; sib pairs Attention-deficit/hyperactivity disorder (ADHD) is a common syndrome first diagnosed in childhood and frequently persistent throughout adult life. Prevalence ranges between 3 and 9% dependent on the nature of the population sampled and the method of ascertainment.1,2 Although heritability estimates are consistently high, averaging around 0.8, ADHD is a genetically complex disorder characterized by multifactorial inheritance involving numerous genes of moderate effect. 2-5While an imbalance in dopaminergic neurotransmission appears to be an important factor predisposing to ADHD, interaction between the dopamine (DA) and serotonin (5-HT) systems has been implicated in both the pathophysiology of ADHD and the mechanism of action of widely used stimulant compounds. By inhibition of the dopamine transporter (DAT), which was reported to be increased in the striatum in ADHD patients, 6 methylphenidate (MPH) is highly effective in reducing the symptoms of ADHD. DAT knockout (KO) mice display a phenotype with increased locomotor activity, 7 which is reversed by MPH-induced increases in 5-HT neurotransmission. 8On the other hand, the hyperlocomotion in DAT KO mice is attenuated by the selective 5-HT reuptake inhibitor (SSRI) fluoxetine or the 5-HT precursor 5-hydroxytryptophan. 9 Early studies reported low platelet 5-HT levels in ADHD patients 10,11 and there is an extensive data base that ADHD-specific syndromal dimensions including impulsive behavior, aggressiveness and substance abuse are linked to alterations

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). Sheehan et al 30 detected a statistically significant association between the T-allele of rs1843809 (intron 5) and ADHD in transmission disequilibrium analysis of 179 Irish families.…”

Pharmacogenetics of antidepressant response

“…[98][99][100] Zhang and colleagues 89 reported that 5-HT levels from cells expressing arginine at position 447 were reduced by about 55% compared with cells expressing proline at position 447. Moreover, in individuals with unipolar major depression, Zhang and colleagues 101 identified a 1463G>A transition in the TPH2 gene.…”

TPH2 gene polymorphisms in the regulatory region are associated with paranoid schizophrenia in Northern Han Chinese

“…However, no evidence has been found for a role of TPH2 in schizophrenia, despite several studies in this area (De Luca et al, 2005a;Higashi et al, 2007;Shiroiwa et al, 2010;Tee et al, 2010;Kim and Yoon, 2011;Zhang et al, 2011). It is noteworthy that a certain number of these studies focused mainly on the rs4570625 (-703G/T), a common polymorphic SNP in the putative promoter (Kennedy et al, 2003) that has been reported to be associated with the attention deficit hyperactivity disorder (ADHD) (Walitza et al, 2005), emotional processing (Herrmann et al, 2007), personality traits, and disorders related to emotional dysregulation (Gutknecht et al, 2007;Reuter et al, 2007). The promoter polymorphism rs4570625 of TPH2 has been also found to affect the responsiveness of the amygdala, a structure critically involved in the regulation of emotional behaviors (Brown et al, 2005;Canli et al, 2005).…”