Linkage and association of the glutamate receptor 6 gene with autism

Abstract

A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism. Molecular Psychiatry Molecular Psychiatry (2002) 7, 302-310.

Linkage and candidate gene studies of autism spectrum disorders in European populations

“…15 Moreover, glutamatergic neurons originate in brain regions implicated in autism, and glutamate antagonists can cause symptoms similar to those of autism. 45 Four studies have specifically looked for association between GRIK2 and autism, with three finding positive evidence 17,18,46 and one study failing to do so. 47 In their recent genome-wide association paper, Wang et al 11 report top associations (Po0.01) for 26 candidate genes.…”

Detailed phenotype–genotype study in five patients with chromosome 6q16 deletion: narrowing the critical region for Prader–Willi-like phenotype

“…Association and linkage studies suggested its involvement in autism. 20,21 Glutamate receptors mediate the majority of excitatory neurotransmission in the brain. 22 Haploinsufficiency of this gene might cause mental retardation.…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…Two studies have found evidence for association of different SNPs in the Glutamate receptor 6 (GluR6) 162,163 Only one of these SNPs might have possible functional implications, and most were located in introns. However, given the importance of glutamate in brain development, learning and memory, 164 the positive linkage findings on 6q21 in two studies (Table 1) as well as post-mortem evidence of brain abnormalities of the glutamate neurotransmitter system in autism, 165 this candidate gene seems to be of relevance in the pathogenesis of AD.…”