Elsevier

Neuroscience Research

Volume 73, Issue 4, August 2012, Pages 333-336
Neuroscience Research

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Association with tryptophan hydroxylase 2 gene polymorphisms and autism spectrum disorders in Korean families

https://doi.org/10.1016/j.neures.2012.05.012Get rights and content

Abstract

It was performed a family-based association study of 6 single nucleotide polymorphisms (SNPs) from the TPH2 with autism spectrum disorder (ASD) in 151 Korean trios. We found a significant association at the rs2129575 with ASD susceptibility (corrected p = 0.006). Furthermore, after conducting with the quantitative scores in the Autism Diagnostic Interview—Revised, there were associations between restricted, repetitive, and stereotyped patterns of behavior (preoccupation with parts of objects or nonfunctional elements of materials) in ASD and SNPs in TPH2. These results suggest that TPH2 polymorphisms influence the phenotypic impairments of ASD and enhance ASD susceptibility.

Highlights

► The associations between SNPs in TPH2 and Korean ASD were examined. ► We found a significant association at the rs2129575 with ASD susceptibility. ► TPH2 polymorphisms may influence ASD susceptibility and the phenotypic impairments.

Introduction

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that manifests early in development as social reciprocity inadequacies, verbal and nonverbal communication deficits, and repetitive and stereotypic behaviors (Folstein and Rosen-Sheidley, 2001). Serotonin (5-hydroxytryptamine, 5-HT) is the major monoamine neurotransmitter existed in the serotonergic neurons of the raphe nuclei as a source of serotonin in the forebrain. Abnormalities of the serotonin system have been implicated in autism, as evidenced by elevated levels of serotonin in autistic children versus non-autistic subjects (Cook et al., 1988), an aggravation of stereotyped and repetitive behaviors with tryptophan depletion (McDougle et al., 1996), and lower plasma levels of tryptophan in subjects with autism compared to controls (Croonenberghs et al., 2000).

The TPH2 (tryptophan hydroxylase 2) is a rate-limiting enzyme that catalyzes the first step of 5-HT biosynthesis through 5-hydroxytryptophan from tryptophan and encoded by THP2 (tryptophan hydroxylase 2 gene) located on chromosome 12q21.1 (Patel et al., 2004; Walther et al., 2003). As TPH2 plays a central role in the maintenance and regulation of serotonin levels, polymorphism studies for the TPH2 have helped to find new mutations and associations with neuropsychiatric disorders (Shiroiwa et al., 2010, Yoon and Kim, 2009). It has been reported that the exonic variants related to mental diseases were correlated with overall changes in the TPH2 allele expression level in sections of the human pons and the dorsal and median raphe nuclei (Lim et al., 2007). The promoter variants of TPH2, rs11178996 and rs4570625, also affected gene expression in cultured human cell systems as well as in the raphe nuclei of the rat (Scheuch et al., 2007).

Coon et al. (2005) reported significant associations between the SNPs of TPH2 and autism in Caucasian populations and suggested that the 2 SNPs (rs4341581 and rs11179000) are related to high scores of repetitive and stereotyped behaviors from the Autism Diagnostic Interview (ADI-R). In a replication study by Ramoz et al. (2006), the 8 TPH2 SNPs, identified by Coon et al. (2005), were investigated along with the SNPs of the TPH1. However, no association was found after performing a transmission disequilibrium test (TDT) for multiplex families and a subset of trios containing autistic children consisted with unmatched population for the TPH2 but not TPH1. Mostly, Sacco et al. (2007) examined the association for selected SNPs (rs4570625 and rs4565946) using case-control and TDT designs within Italian and Caucasian-American trios. Although various attempts were made to associate autistic endophenotypes with serotonin blood levels, urinary peptides, head circumference, and qualitative traits of ADI-R, no associations were found between the SNPs of TPH2 and autism susceptibility. Even though there is a discrepancy in autism association results, variants of TPH2 have been consistently implicated as the strongest genetic markers for the neuropsychiatric traits seen in autism.

The aim of this study was to investigate the association between 6 SNPs of the TPH2 in Koreans with ASD and to evaluate the relationship of TPH2 genotypes with quantitative trait characterized by a diagnostic algorithm.

Section snippets

Subjects

Ascertainment of ASD subjects and diagnostic procedure has been previously described in our family-based genetic association study (Cho et al., 2007, Yoo et al., 2009). In brief, children with ASD were clinically evaluated using DSM-VI diagnostic criteria, including DSM-VI scales of intelligence and social maturity, and then confirmed by the Korean version of the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview—Revised (ADI-R). Subjects with organic brain disease,

Results

Hardy–Weinberg equilibrium was checked for these SNPs in all samples and met the criteria. The rs11178996 and rs4570625 in the 5′ flanking region revealed strong linkage disequilibrium (LD) (D = 0.97). The remaining 4 were as follows: 2 intronic SNPs at intron 4 (rs2129575) and intron 8 (rs1352250) and the two synonymous SNPs at exon 7 (rs7305115) and exon 9 (rs4290270) showed moderate D′ value (0.80–0.37) (Supplementary Table 1).

In family-based association test, although the six SNPs were not

Discussion

The abnormality of serotonin levels in the cortex and hypothalamus of autistic individuals have consistently been mentioned (Chugani et al., 1997, Cook and Leventhal, 1996, Warren and Singh, 1996) and reported about involvement of compulsive and stereotyped behaviors (Hollander et al., 2000). Moreover, repetitive behavior, a representative phenotype of autistic children, has been shown to be regulated by serotonin-enhancing medications such as selective serotonin reuptake inhibitors (SSRIs) and

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (2010-0007583). Mira Park was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2007-531-C00018).

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