Elsevier

Neuroscience Research

Volume 68, Issue 2, October 2010, Pages 137-141
Neuroscience Research

Further evidence for the role of MET in autism susceptibility

https://doi.org/10.1016/j.neures.2010.06.014Get rights and content

Abstract

MET receptor tyrosine kinase (MET)-mediated signaling has been implicated in multiple aspects of neocortical and cerebellar neuronal growth and maturation. A promoter functional SNP (rs1858830) that disrupts the transcription of MET has been reported to be strongly associated with autism spectrum disorders (ASD) in the Caucasian population. Here, we performed a trio association study of MET with ASD in Japanese subjects (n = 126 trios). Based on the HapMap data on the Japanese population, 15 SNPs were chosen for the association study. One SNP located in intron 1, rs38841, showed a nominal association with autism (p = 0.044; OR = 1.61) when analyzed using the transmission disequilibrium test. To the best of our knowledge, this is the first replication study of the association of MET with autism, in any non-Caucasian population. Association of rs38841 with autism was further confirmed in 252 Caucasian trios from AGRE (p = 0.0006). An interesting observation is that all three SNPs of MET (rs1858830, rs38845 and rs38841) shown to be associated with autism in three independent studies including the present one, are located towards the 5′end of the gene at a span of 9.4 kb. Our results provide further evidence for a possible role of MET in the pathogenesis of ASD.

Introduction

Autism is a prevalent neurodevelopmental disorder defined by profound impairments in the emergence of social behaviors and communication, traditionally diagnosed by the age of 3 years. Restricted interests and repetitive and stereotyped behaviors are also prominent features of the disorder (Lord et al., 2000). Although, once considered to be relatively rare, recent estimates show a prevalence of 1 in 500 for a strict diagnosis and 1 in 150 using broader diagnostic criteria (Kuehn, 2007). Though this alarming increase in prevalence can be attributed partly to the broadening of diagnostic criteria and improvement of diagnostic capacity (Steyaert and De la Marche, 2008), it emphasizes the pressing urgency for determining the etiology of autism, which remains still largely cryptic.

An armamentarium of techniques and tools developed in the last decade provides several lines of evidence that support the role of genetic factors in the etiology of autism. Defining mutations and structural variations in any of several genes increases the disease risk in many reports (Losh et al., 2008). Family and twin studies have generated overwhelming evidence about the high heritability of autism spectrum disorders. Gene association studies, whole genome linkage studies and genome wide techniques to identify copy number variations showed genetic causes for about 10–20% of ASD cases, at present (Abrahams and Geschwind, 2008). However, none of these known causes individually account for more than 1–2% of the cases, depicting the genetic heterogeneity of the disorder, which made identification of a common genetic variant a near impossible task.

A promoter functional SNP, rs1858830, that disrupts the transcription of the MET receptor tyrosine kinase (MET) gene, which is located in a common autism linkage region, chromosome 7q31, has been reported to be strongly associated with autism in a family based association study consisting of 204 autism families of Caucasian origin (Campbell et al., 2006). The finding was replicated in a sample of 539 autism families (combined p = 5 × 10−6). Case–control comparisons found significant overrepresentation of the ‘C’ allele in autism with a relative risk of 2.27. It was found that the ‘C’ variant causes an altered binding of specific transcription factor complexes that result in a two-fold decrease in MET promoter activity (Campbell et al., 2006). Signaling mediated by MET and its single known ligand, hepatocyte growth factor (HGF), has been implicated in a variety of physiological, developmental and repair processes (Birchmeier et al., 2003).

The importance of MET signaling in the pathophysiology of autism has begun to be recognized. The findings of Campbell et al. (2006) represent the first robust connection of a functional genetic variant with idiopathic autism and replication studies in different populations are warranted (State, 2006). Previously we reported significantly reduced levels of HGF in the serum samples of Japanese autistic patients compared to age-matched controls (Sugihara et al., 2007). Here, we performed a trio-based study to examine the association of MET with autism in Japanese subjects and tried to replicate our findings in Caucasian trio families.

Section snippets

Subjects

The subjects included 126 children with ASD [diagnosis: 118 autism, 8 pervasive developmental disorder not otherwise specified; sex: 107 males, 19 females; age: 10.49 ± 4.75 (mean ± SD); IQ: 82.06 ± 26.6] and their parents (total 378 individuals). The purpose of the study was fully explained to the participants, and written informed consent was obtained. The study was approved by the ethics committees of the participating institutes.

Based on interviews and available information including the hospital

Single SNP TDT

Mendelian inheritance inconsistencies were not observed for any of the SNPs. For each SNP, >99% of the genotypes were scored; none of the SNPs showed deviation from HWE.

The results of TDT analysis are shown in Table 1. rs38841 showed nominal association with autism (p = 0.044; OR = 1.61; 95% CI 1.01–2.58). The major allele (A) of rs38841 showed over-transmission (52.04%). However, this does not withstand the multiple testing correction. The promoter functional variant rs1858830 which showed strong

Discussion

In this study, we examined the association of the HGF receptor MET with autism in the Japanese population. Though limited by small sample size, our study is to the best of our knowledge, the first replication study on any non-Caucasian population involving the association of MET with autism since Campbell et al. (2006) reported a robust association for a promoter functional variant (rs1858830) in Caucasian autism samples. However, in our trio-based study, we could not find any association for

Acknowledgments

We gratefully acknowledge the support of the Autism Genetic Resource Exchange program (www.agre.org). This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Prof. Pat Levitt for his advice.

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    The first three authors contributed equally to this work.

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