Human Gene Module / Chromosome 6 / GRIK2

GRIK2glutamate ionotropic receptor kainate type subunit 2

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
11 / 18
Rare Variants / Common Variants
11 / 10
Aliases
GRIK2, EAA4,  GLR6,  GLUR6,  MGC74427
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
6q16.3
Associated Disorders
-
Relevance to Autism

Studies have found genetic association between the GRIK2 gene and autism. Positive associations have been found in the Chinese Han population among others. No association between GRIK2 and autism was found in an Indian population sample, however.

Molecular Function

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Mutations in this gene have been associated with autosomal recessive cognitive disability.

Reports related to GRIK2 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Linkage and association of the glutamate receptor 6 gene with autism. Jamain S , et al. (2002) Yes -
2 Positive Association Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Shuang M , et al. (2004) Yes -
3 Recent Recommendation Glutamate receptor agonist kainate enhances primary dendrite number and length from immature mouse cortical neurons in vitro. Monnerie H and Le Roux PD (2006) No -
4 Recent Recommendation Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate. Weston MC , et al. (2006) No -
5 Negative Association Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: a genetic association study on autism spectrum disorder. Dutta S , et al. (2007) Yes -
6 Positive Association Linkage and candidate gene studies of autism spectrum disorders in European populations. Holt R , et al. (2010) Yes -
7 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
8 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
9 Support Expanding the spectrum of Grik2 mutations: intellectual disability, behavioural disorder, epilepsy and dystonia. Crdoba M , et al. (2014) No -
10 Positive Association A candidate gene association study further corroborates involvement of contactin genes in autism. Poot M (2014) Yes -
11 Positive Association Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos... Namjou B , et al. (2014) Yes -
12 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
13 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
14 Support A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits. Guzmn YF , et al. (2017) No Microcephaly, hypotonia, ataxia, stereotypic behav
15 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. Chen R , et al. (2017) Yes -
16 Support Both rare and common genetic variants contribute to autism in the Faroe Islands. Leblond CS , et al. (2019) Yes -
17 Highly Cited Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Rubinsztein DC , et al. (1997) No -
18 Highly Cited Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Mulle C , et al. (1998) No -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
insA - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
A>G - missense_variant De novo - Simplex 28344757 Chen R , et al. (2017)
c.1969G>A p.Ala657Thr missense_variant De novo - - 28180184 Guzmn YF , et al. (2017)
C>A p.Asn654Lys missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
- p.Leu888Ter stop_gained Familial Maternal Simplex 30675382 Leblond CS , et al. (2019)
- p.Leu888Ter stop_gained Familial Paternal Simplex 30675382 Leblond CS , et al. (2019)
c.1261C>T p.Pro421Ser missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.[592C>T];[592C>T] p.[Arg198Ter];[Arg198Ter] stop_gained;stop_gained Familial Both parents Multiplex 25039795 Crdoba M , et al. (2014)
Common Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2424G>A;c.2277G>A;c.1809G>A;c.1863G>A p.(=) synonymous_variant - - - 15389769 Shuang M , et al. (2004)
c.2312-9C>T;c.2165-9C>T;c.1697-9C>T;c.1751-9C>T N/A intron_variant - - - 15389769 Shuang M , et al. (2004)
c.-1660G>A;c.-293-1367G>A Minor allele, A intron_variant, 2KB_upstream_variant - - - 25477900 Namjou B , et al. (2014)
c.116-52158T>C - intron_variant - - - 25337070 Poot M (2014)
C/T N/A intron_variant - - - 11920157 Jamain S , et al. (2002)
G/A p.(=) synonymous_variant - - - 11920157 Jamain S , et al. (2002)
c.724-219G>A;c.577-219G>A A/G intron_variant - - - 25337070 Poot M (2014)
c.951+23586G>T;c.804+23586G>T - intron_variant - - - 25337070 Poot M (2014)
c.2601G>A p.Met867Ile missense_variant - - - 11920157 Jamain S , et al. (2002)
c.116-88046T>C;c.116-88047T>C - intron_variant - - - 20442744 Holt R , et al. (2010)
SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Increased from 3 to 4.3 + acc2

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2018
3
icon
4.3 + acc2

Increased from 3 to 4.3 + acc2

Description

3

4/1/2017
3
icon
3

Increased from 3 to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

Reports Added
[Linkage and association of the glutamate receptor 6 gene with autism.2002] [Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.2004] [Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: a genetic association study on autism spectrum disorder.2007] [Linkage and candidate gene studies of autism spectrum disorders in European populations.2010] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos...2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Expanding the spectrum of Grik2 mutations: intellectual disability, behavioural disorder, epilepsy and dystonia.2014] [Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease.1997] [Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice.1998] [Glutamate receptor agonist kainate enhances primary dendrite number and length from immature mouse cortical neurons in vitro.2006] [Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate.2006] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits.2017] [Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.2017]
1/1/2017
3
icon
3

Increased from 3 to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

10/1/2016
3
icon
3

Increased from 3 to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

1/1/2015
3
icon
3

Increased from 3 to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

10/1/2014
3
icon
3

Increased from 3 to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

7/1/2014
No data
icon
3

Increased from No data to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

4/1/2014
No data
icon
3

Increased from No data to 3

Description

There are multiple association results that do not reach genome-wide significance to date. There are associations with other diseases, such as schizophrenia and obsessive-compulsive disorder, which boost the gene from category 4 to category 3.

Krishnan Probability Score

Score 0.61345831236162

Ranking 142/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.9945679541127

Ranking 1555/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.92004157452794

Ranking 9111/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 7

Ranking 243/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.34717213279251

Ranking 2055/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with GRIK2(1 CNVs)
6q16.3 15 Deletion-Duplication 24  /  42
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
GRIK4 glutamate receptor, ionotropic, kainate 4 Mouse Protein Binding 110637 Q8BMF5
LIN7A lin-7 homolog A (C. elegans) Mouse Protein Binding 108030 Q8JZS0
Submit New Gene

Report an Error