Association of the glutamate receptor subunit gene <i>GRIN2B</i> with attention‐deficit/hyperactivity disorder

Dorval, Kimberley M.; Wigg, Karen; Crosbie, Jennifer; Tannock, Rosemary; Kennedy, James L.; Ickowicz, Abel; Pathare, Tejaswee; Malone, Molly; Schachar, Russell; Barr, Cathy L.

doi:10.1111/j.1601-183x.2006.00273.x

Cited by 103 publications

(82 citation statements)

References 75 publications

(88 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both GRM5 and GRM7 (above) belong to the glutamatergic receptor gene family hypothesized to play a role in ADHD. [43][44][45] The GRM5 variant, a hemizygous deletion of 82 kb (11 SNPs; Supplementary Figure S2), showed uniparental inheritance and was experimentally validated by FISH (Figure 1). Neuropsychiatric assessment indicated that all three children in this family, one 18-year-old male and two females with ages 15 and 11, met the criteria for Table 2 are listed in the Supplementary Materials.…”

Section: Resultsmentioning

confidence: 98%

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

et al. 2009

View full text Add to dashboard Cite

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

show abstract

Section: Resultsmentioning

confidence: 98%

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

et al. 2009

View full text Add to dashboard Cite

show abstract

“…cerebral cortex ͉ glutamatergic signaling ͉ regulatory RNA N MDA receptors (NMDA-R) control many executive brain functions, such as working memory, and their dysfunction is implicated in a host of brain disorders (1)(2)(3)(4). Notably, hypofunctional NMDA-R signaling, particularly in the prefrontal cortex (PFC), has been implicated in the cognitive and behavioral disturbances characteristic of schizophrenia (5), autism (6,7), attention deficit hyperactivity disorder (ADHD) (8,9), mood disorders (10), and other psychiatric illnesses.…”

mentioning

confidence: 99%

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Kocerha

Faghihi

López‐Toledano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

268

218

View full text Add to dashboard Cite

cerebral cortex ͉ glutamatergic signaling ͉ regulatory RNA N MDA receptors (NMDA-R) control many executive brain functions, such as working memory, and their dysfunction is implicated in a host of brain disorders (1-4). Notably, hypofunctional NMDA-R signaling, particularly in the prefrontal cortex (PFC), has been implicated in the cognitive and behavioral disturbances characteristic of schizophrenia (5), autism (6, 7), attention deficit hyperactivity disorder (ADHD) (8, 9), mood disorders (10), and other psychiatric illnesses. The cellular mechanisms by which disrupted NMDA-R transmission drives behavioral pathology are still unclear, although several of the major proteins involved in this pathway, such as calcium/calmodulin-dependent protein kinase II (CaMKII) (11), have been identified. In this study, we examine whether neurobehavioral abnormalities associated with NMDA-R hypofunction can be attributed to a novel class of regulatory RNA molecules, microRNAs (miRNAs).miRNAs have attracted much attention as regulators of neuronal development and synaptic plasticity (12-15). Furthermore, psychiatric disorders such as schizophrenia, autism, and Tourette's syndrome are associated with dysregulated levels of miRNAs (16)(17)(18)(19)(20). miRNAs are small (Ϸ22 nt) noncoding transcripts that can control expression of protein-coding mRNAs at the posttranscriptional level (21). Pleiotropic miRNAs can control gene expression by binding to complementary sequences in the 3Ј untranslated region (3Ј UTR) of target mRNA transcripts to facilitate their degradation and/or inhibit their translation (15,22,23). Understanding this layer of gene regulation therefore promises to enrich our knowledge of brain function and pathology. Dizocilpine is a highly selective phencyclidine-like NMDA-R antagonist that can rapidly produce schizophrenia-like behavioral deficits in humans and rodents (24). We examined whether a psychotomimetic dose of dizocilpine (0.5 mg/kg, i.p.) altered miRNA expression in brain regions of C57BL/6 mice, by using miRNA microarray profiling as an initial screening approach. Our analysis was focused on the PFC because of the considerable evidence linking this brain region with behavioral pathology in psychiatric illnesses (19). We extracted the small RNAs from the PFC of the mice 15 min after administration of a single dose of dizocilpine, i.e., a time-point at which dizocilpine-induced behavioral disturbances such as hyperlocomotion and stereotypy are readily observed (25). Of note, there was a robust reduction of miR-219 out of 182 miRNAs detectable by microarray in PFC tissues (Table S1). miR-219 is a conserved miRNA expressed in both rodent and human brains, but not in other tissues (26,27). These data demonstrate that concentrations of a brain-specific miRNA, which may play a role in regulating NMDA-R function, are altered during states of NMDA-R hypofunction.In support of the microarray data, RT-PCR analyses demonstrated that miR-219 levels were significantly reduced by Ϸ50% (a change from an average cycle th...

show abstract

“…Genetic variations of GRIN2B have been implicated in the genetic susceptibility to neuropsychiatric disorders other than OCD, including attention-deficit/hyperactivity disorder, 53 dyslexia, 54 schizophrenia and bipolar disorder (for a review, see Cherlyn and colleagues 34 ). Moreover, Parkinson disease and Huntington disease, 2 neurologic conditions in which obsessive-compulsive symptoms are not rare, have also been associated with changes in the function of the NR2B-containing NMDA receptors (for a review, see Loftis and Janowsky…”

mentioning

confidence: 99%

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

Alonso

Gratacòs

Segalás

et al. 2012

jpn

View full text Add to dashboard Cite

Background: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. Methods: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. Results: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. Limitations: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B. Conclusion: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.

show abstract

Association of the glutamate receptor subunit gene GRIN2B with attention‐deficit/hyperactivity disorder

Cited by 103 publications

References 75 publications

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

Contact Info

Product

Resources

About