Human Gene Module / Chromosome 1 / GRIK3

GRIK3glutamate ionotropic receptor kainate type subunit 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 7
Rare Variants / Common Variants
5 / 0
Aliases
GRIK3, EAA5,  GLR7,  GLUR7,  GluK3,  GluR7a
Associated Syndromes
-
Chromosome Band
1p34.3
Associated Disorders
-
Relevance to Autism

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014).

Molecular Function

Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRIK3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia Begni S , et al. (2002) No -
2 Negative Association No association between the ionotropic glutamate receptor kainate 3 gene ser310ala polymorphism and schizophrenia Lai IC , et al. (2005) No -
3 Positive Association Association between the ionotropic glutamate receptor kainate3 (GRIK3) Ser310Ala polymorphism and schizophrenia in the Indian population Ahmad Y , et al. (2009) No -
4 Primary Integrated systems analysis reveals a molecular network underlying autism spectrum disorders Li J , et al. (2015) Yes -
5 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
6 Support Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities Koromina M , et al. (2019) Yes -
7 Support - Zhou X et al. (2022) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.914A>G p.Gln305Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1928G>T p.Trp643Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1910T>C p.Ile637Thr missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1756T>G p.Phe586Val missense_variant Unknown - Unknown 31844109 Koromina M , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The GRIK3 non-synonymous variant identified in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or dbSNP and had a high GERP++ conservation score (4.88). A de novo missense variant in GRIK3 was identified in an ASD proband in Lim et al., 2017. A p.Ser310Ala polymorphism in GRIK3 has been found to associate with schizophrenia in Italian and Indian populations (Begni et al., 2002; Ahmad et al., 2009), although this association was not observed in a Chinese schizophrenia cohort (Lai et al., 2005).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The GRIK3 non-synonymous variant identified in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or dbSNP and had a high GERP++ conservation score (4.88). A de novo missense variant in GRIK3 was identified in an ASD proband in Lim et al., 2017. A p.Ser310Ala polymorphism in GRIK3 has been found to associate with schizophrenia in Italian and Indian populations (Begni et al., 2002; Ahmad et al., 2009), although this association was not observed in a Chinese schizophrenia cohort (Lai et al., 2005).

1/1/2020
3
icon
3

Decreased from 3 to 3

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The GRIK3 non-synonymous variant identified in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or dbSNP and had a high GERP++ conservation score (4.88). A de novo missense variant in GRIK3 was identified in an ASD proband in Lim et al., 2017. A p.Ser310Ala polymorphism in GRIK3 has been found to associate with schizophrenia in Italian and Indian populations (Begni et al., 2002; Ahmad et al., 2009), although this association was not observed in a Chinese schizophrenia cohort (Lai et al., 2005).

Reports Added
[Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities.2019]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The GRIK3 non-synonymous variant identified in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or dbSNP and had a high GERP++ conservation score (4.88). A de novo missense variant in GRIK3 was identified in an ASD proband in Lim et al., 2017. A p.Ser310Ala polymorphism in GRIK3 has been found to associate with schizophrenia in Italian and Indian populations (Begni et al., 2002; Ahmad et al., 2009), although this association was not observed in a Chinese schizophrenia cohort (Lai et al., 2005).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The GRIK3 non-synonymous variant identified in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or dbSNP and had a high GERP++ conservation score (4.88). A de novo missense variant in GRIK3 was identified in an ASD proband in Lim et al., 2017. A p.Ser310Ala polymorphism in GRIK3 has been found to associate with schizophrenia in Italian and Indian populations (Begni et al., 2002; Ahmad et al., 2009), although this association was not observed in a Chinese schizophrenia cohort (Lai et al., 2005).

Reports Added
[Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia.2002] [No association between the ionotropic glutamate receptor kainate 3 gene ser310ala polymorphism and schizophrenia.2005] [Association between the ionotropic glutamate receptor kainate3 (GRIK3) Ser310Ala polymorphism and schizophrenia in the Indian population.2009]
Krishnan Probability Score

Score 0.57005866111961

Ranking 976/25841 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.
Original Source
ExAC Score

Score 0.99998017016386

Ranking 506/18225 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
Original Source
Sanders TADA Score

Score 0.94136581124259

Ranking 14906/18665 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).
Original Source
Zhang D Score

Score 0.3932021098727

Ranking 1537/20870 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.
Original Source
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