Family‐based association testing of OCD‐associated SNPs of SLC1A1 in an autism sample

Abstract

Reports identified the neuronal glutamate transporter gene, SLC1A1 (OMIM 133550, chromosome 9p24), as a positional and functional candidate gene for obsessive-compulsive disorder (OCD). The presence of obsessions and compulsions similar to OCD in autism, the identification of this region in a genome-wide linkage analysis of individuals with autism spectrum disorders (ASDs), and the hypothesized role of glutamate in ASDs make SLC1A1 a candidate gene for ASD as well. To test for association between SLC1A1 and autism, we typed three single nucleotide polymorphisms (SNPs, rs301430, rs301979, rs301434) previously associated with OCD in 86 strictly defined trios with autism. Family-Based Association Tests (FBAT) with additive and recessive models were used to check for association. Additionally, an rs301430-rs301979 haplotype identified for OCD was investigated. FBAT revealed nominally significant association between autism and one SNP under a recessive model. The G allele of rs301979 was undertransmitted (equivalent to overtransmission of the C allele under a dominant model) to individuals with autism (Z 5 À2.47, P 5 0.01). The G allele was also undertransmitted in the T-G haplotype under the recessive model (Z 5 À2.41, P 5 0.02). Both findings were also observed in the male-only sample. However, they did not withstand correction for multiple comparisons.

Family-based association testing of glutamate transporter genes in autism

“…Four glutamate transporter genes, SLC1A1 , SLC1A2 , SLC1A3 , and SLC1A6 , are positional and functional candidates for autism. Studies have implicated SLC1A1 in obsessive compulsive disorder (Arnold et al 2006) and autism spectrum disorder (ASD) (Brune et al 2008). Up-regulation of SLC1A2 and SLC1A3 has been reported in brains of individuals with autism (Purcell et al 2001).…”

Brief Report: Glutamate Transporter Gene (SLC1A1) Single Nucleotide Polymorphism (rs301430) and Repetitive Behaviors and Anxiety in Children with Autism Spectrum Disorder

“…The percentage of youths with the C/C genotype was small, and though consistent with no-nASD samples, increased the risk of a Type 2 error. Moreover, gene-behavior relations may have been more evident had we examined a wider array of SNPs or conducted haplotype analyses (e.g., Brune et al 2008; Dickel et al 2006; Wendland et al 2009; Stewart et al 2007). For example, it is possible that other loci, some of which in linkage disequilibrium with rs301430, would provide stronger evidence of or better explanation for an association with OCB severity.…”

“…The glutamate transporter gene ( SLC1A1 ), which encodes the neuronal glutamate transporter excitatory amino acid carrier 1, is highly expressed in regions of the brain that are implicated in the pathogenesis of OCD (Arnold et al 2006; Brune et al 2008; Dickel et al 2006; Stewart et al 2007; Wendland et al 2009). The glutamate transporter regulates neurotransmission by removing glutamate from the extracellular space thus terminating synaptic transmission.…”

“…Others, however, have not found differences in allele frequencies between child-onset OCD cases and controls for rs301430 (Wang et al 2009). In one of the few studies to investigate its potential role in ASD pathogenesis, Brune et al (2008) found preliminary evidence for differential transmission of a haplotype that included rs301430.…”

Advanced Pharmacotherapy Evidenced by Pathogenesis of Autism Spectrum Disorder

“…Yip et al22) reported consistent findings regarding increase in glutamate concentration due to fewer Purkinje cells in autistic cerebella and related enzymes. Second, there are proposals suggesting that glutamate transporters (excitatory amino acid transporters), which translocate glutamate from endothelial cells to the extracellular fluids, are involved in autism's pathophysiology 23). Third, Brown et al24) and Ortinski et al25) reported that decreased glutamine and increased glutamate due to dysfunctions in the glutamate-glutamine cycle is significantly involved in ASD development.…”