Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: A case-control study

Abstract

Autism (MIM 209850) is a severe neurodevelopmental disorder characterized by disturbances in social interaction and communication, by repetitive body movements and restricted interests, and by atypical language development. Several twin and family studies have shown strong evidence for genetic factors in the etiology of autism. Glutamate is a major excitatory neurotransmitter in the human brain. Glutamate systems are involved in the pathophysiology of autism. There are many similarities between the symptoms evoked by glutamate antagonist treatment and symptoms of autism found in several human and animal studies. To elucidate the genetic background of autism, we analyzed the relationship between three single nucleotide polymorphisms (SNPs) of the Tachykinin 1 gene (TAC1) and autism, because TAC1 is located in the candidate region for autism and produces substance P and neurokinins. These products modulate glutamatergic excitatory synaptic transmission and are also involved in inflammation. Many different inflammation-related mechanisms could be involved in the autistic brain. Therefore, TAC1 may have some functions associated with the presumable pathophysiology of autism. We compared the allele and haplotype frequencies between autistic patients (n = 170) and normal controls (n = 214) in the Japanese population, but no significant difference was observed. Thus, the TAC1 locus is not likely to play a major role in the development of autism.

Introduction

Autism is a neurodevelopmental disorder characterized by early onset of the three cardinal symptoms: disturbance of social interaction, atypical language development, and restricted, repetitive, stereotyped patterns of behavior and interests [1]. The genetic involvement of autism has been supported by its higher concordance rates for monozygotic twins than for dizygotic [2], [3] and the several chromosomal loci possibly linked to autism, including 7q22-q31 [1].

Glutamate is one of the neurochemicals speculated to contribute to the pathogenesis of autism, because (1) there are many similarities between the symptoms evoked by glutamate antagonist treatment and the symptoms of autism found in several human and animal studies [4]; (2) several neuropathological and brain-imaging studies of autistic patients have shown involvement of the cerebral regions where glutamatergic neurons originate [4]; (3) the mRNA levels of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor increases in autistic subjects [5]; (4) the aspartate/glutamate carrier SLC25A12 gene and metabotropic glutamate receptor 8 gene have been reported to be associated with autism [6], [7].

In this study, we focused on the Tachykinin 1 gene (TAC1; MIM162320) because it is located in 7q21-q22 and encodes a precursor containing substance P and other neurokinins (Neurokinin A, Neurokinin K, and Neuropeptide γ) [8], some of which are implicated in the modulation of glutamate-driven neurotransmission and excitotoxicity in the basal forebrain and other CNS regions [9]. Moreover, TAC1 mutant mice are less sensitive to nociceptive stimulation, which reminds us of some autistic patients ignorant of pain [4], [11]. An increase in proinflammatory cytokines and the activation of microglia and astrocytes in the brain of autistic patients may be also associated with the inflammatory responses of TAC1 products [12].

Based on TAC1 biological information and its chromosomal location, we considered the gene worth analyzing as one of the autism candidate genes. In the present study, we tested for the presence of an association of three single nucleotide polymorphisms (SNPs) of TAC1, and haplotypes consisting of the SNPs, with autism, using case-control design.