Research ReportFamily-based association study of 5-HTTLPR and the 5-HT2A receptor gene polymorphisms with autism spectrum disorder in Korean trios
Introduction
The potential role of the serotoninergic system in the development of autistic disorder has long been suggested (Maestrini et al., 1999, Anderson, 2002, Andres, 2002), based on the observation of hyperserotoninemia in autistic subjects (Schain and Freedman, 1961, Anderson et al., 1987, Abramson et al., 1989, Cook and Leventhal, 1996). Furthermore, drug treatment studies have indicated that selective serotonin reuptake inhibitor drugs (SSRIs) can effectively improve some symptoms such as repetitive behavior, aggression, and language use in individuals with autistic disorder (Gordon et al., 1993, McDougle et al., 1996, Anderson, 2002).
The serotonin transporter gene (SLC6A4) is considered one of the most widely studied candidate genes in autism spectrum disorder (ASD). It has been reported that this gene contains two polymorphisms in its promoter region (5-HTTLPR) and a variable number of tandem repeat (VNTR) in its second intron (Heils et al., 1996, Lesch et al., 1994). In recent studies, the association between 5-HTTLPR and ASD has produced controversial results depending on ethnic diversity, methods of genetic analysis, and symptom profiles of ASD (Zhong et al., 1999, Persico et al., 2000, Yirmiya et al., 2001, Kim et al., 2002, Persico et al., 2002, Conroy et al., 2004, McCauley et al., 2004).
Recently, serotonin receptor genes have been studied as the other candidate genes of ASD in the serotonin system. In particular, the 5-HT2A receptor gene (HTR2A) was recognized as one of the most plausible functional candidate genes of ASD (Veenstra-VanderWeele et al., 2002). Previous association studies were performed to examine the relationship between two single nucleotide polymorphisms (SNPs) (-1438G/A and 102T/C) in HTR2A and various psychiatric disorders, especially schizophrenia and affective disorder, as well as that between the autistic disorder and these SNPs (Inayama et al., 1996, Massat et al., 2000, Veenstra-VanderWeele et al., 2002). With regard to the functional aspects, McBride et al. (1989) observed that autistic subjects had substantially blunted prolactin release in response to a 60-mg oral dose of fenfluramine hydrochloride, which is an indirect serotonin agonist. Furthermore, the magnitude of serotonin-amplified platelet aggregation, mediated by the platelet 5-HT2 receptor complex, was reduced in autistic subjects, as was the mean number of platelet 5-HT2 receptor sites. Another study reported that the binding of 3H-lysergic acid diethylamine (3H-LSD), which is a 5-HT2A partial agonist, was lower in hyperserotoninemic first-degree relatives of autistic patients than in normoserotoninemic first-degree relatives (Cook et al., 1993b). In a serotonin-related drug study, it was shown that the 5-HT2A receptor gene polymorphism was associated with a high number of side effects in autistic patients in the Japanese population (Sugie et al., 2003).
In this study, by using the transmission disequilibrium test (TDT), we conducted a family-based association study of 5-HTTLPR and the two SNPs of HTR2A in Korean children with ASD to examine the hypothesis that polymorphisms in SLC6A4 and HTR2A are associated with ASD. This is the first organized association/linkage analysis of ASD in the Korean population.
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Subject characteristics
One hundred and twenty-six complete trios of ASD patients and both biological parents participated in this study. The subjects comprised 109 (86.5%) males and 17 (13.5%) females, and the male-to-female ratio was 6.4:1. Furthermore, 104 (82.5%) patients had autistic disorder, 17 (13.5%) had pervasive developmental disorders not otherwise specified (PDD-NOS), 2 (1.6%) had Asperger's disorder, and 3 (2.6%) had childhood disintegrative disorder. The age of the affected children was 71.9 ± 31.6 (mean ±
Discussion
In the first published association study of 5-HTTLPR and autism using the TDT, Cook et al. (1997) reported the preferential transmission of the short allele in 86 trios of autism (TDT χ2 = 4.69, 1 df, P = 0.030). It is considerably different from our result that shows the preferential transmission of the long allele. In contrast, other studies using TDT analysis revealed significant transmission of the long allele in 35 families of unspecified ethnicity (P = 0.014, 1 df, odds ratio = 2.36) (Yirmiya et
Subjects
Subjects with ASD and their parents were recruited from the Department of Child Psychiatry at Gil Medical Center, Gachon University of Medicine and Science and from Gyeongsang National University Hospital. The ethnic background of all families is Korean, and all parents are the biological parents. The Korean version of Childhood Autism Rating Scale (K-CARS) was used as the screening instrument. All parents were requested to fill out questionnaires regarding the developmental and family history
Acknowledgments
We wish to thank all of the families and special teachers whose participation made this project possible. We also appreciate the help and advice of Dr. Moon Sook Lee, Geonho Bahn, Jae Hyung Park, Jea Hyun Park, and Eun Kyeong Baek. This work was supported by Korea Research Foundation (Grant Number: KPF-2004-002-E00095) and Korean Scientific and Engineering Foundation (Grant Number: R05-2003-000-10295-0). Mira Park was supported by the Korea Research Foundation Grant founded by Korean Government
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