Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD

Abstract

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P ¼ 5 Â 10 À6). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (v 2 ¼ 5.7, P ¼ 0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.

Anti-Ganglioside, Anti-Glutamate, and Anti-Gad Antibody Levels in Attention-Deficit Hyperactivity Disorder

“…In a study by Rout et al (16), it was shown that there is a relationship between GAD65 and disease in autism and ADHD. In another study, it was suggested that the GRIN2A gene polymorphism may be a risk factor for ADHD (18). In our study, no significant relationship was found among ADHD and levels of anti-ganglioside antibodies, anti-glutamate receptor antibodies, and anti-GAD antibodies.…”

“…In addition, there has been an increase in the number of studies evaluating autoimmunity in the etiology of psychiatric diseases such as obsessive compulsive disorder, Tourette syndrome, and anorexia nervosa (13)(14)(15). Antibodies against glutamate NMDA receptors, GAD, and gliadin are closely related to CNS disorders (16,18). Brain areas, in which auto-antibodies have a direct effect include the hypothalamus, hippocampus, amygdala, and limbic system components and these areas account for emotional response and memory.…”

“…In animal studies, it was found that there is a relationship between glutamate receptors related to motor activity and ADHD. It was also suggested that Glutamate Receptor, Ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene polymorphisms may be a risk factor for ADHD (18). In literature, there is no study investigating the relationship between the anti-ganglioside antibodies and ADHD.…”

A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability

“…Our interest was also fueled by the observation that the SSADH gene maps to a region of the genome (6p22), showing both genetic linkage and genetic association to the cognitive phenotype dyslexia. 10 We used two different designs to test for an association between SSADH and intelligence in order to reduce the possibility of a false-positive association and to control for stratification: a case-control design and a transmission disequilibrium test (TDT) design consisting of parent-offspring trios.…”

Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region

“…2 We tested for linkage between the alleles and haplotypes of four polymorphisms at the GRIN2A locus and ADHD in our sample of 183 nuclear families with 229 affected children. In contrast to previous findings, we did not identify any evidence for a relationship of these markers and ADHD.…”