Human Gene Module / Chromosome 6 / GLO1

GLO1glyoxalase I

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 10
Rare Variants / Common Variants
2 / 5
Aliases
GLO1, GLYI
Associated Syndromes
-
Chromosome Band
6p21.2
Associated Disorders
-
Relevance to Autism

Genetic association has been found between the GLO1 gene and autism (Junaid et al., 2004; Kovac et al., 2014). However, no genetic association was found between GLO1 and autism in Finnish, Italian and Caucasian-American population cohorts. Separately, genetic association was found between GLO1 and panic disorder without agoraphobia in an Italian population cohort (Politi et al., 2006).

Molecular Function

The encoded protein mediates catalysis and formation of S-lactoyl-glutathione from methylglyoxal and reduced glutathione.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GLO1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Glyoxalase I is involved in resistance of human leukemia cells to antitumor agent-induced apoptosis Sakamoto H , et al. (2000) No -
2 Primary Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor Junaid MA , et al. (2004) Yes -
3 Recent Recommendation Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice Hovatta I , et al. (2005) No -
4 Recent Recommendation Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder Politi P , et al. (2005) No -
5 Negative Association Case-control and family-based association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1 Sacco R , et al. (2007) Yes -
6 Negative Association No association between common variants in glyoxalase 1 and autism spectrum disorders Rehnstrm K , et al. (2007) Yes -
7 Support Glyoxalase I polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity--implications for autism Barua M , et al. (2011) No -
8 Positive Association Weak association of glyoxalase 1 (GLO1) variants with autism spectrum disorder Kova J , et al. (2014) Yes -
9 Positive Association The GLO1 C332 (Ala111) allele confers autism vulnerability: family-based genetic association and functional correlates Gabriele S , et al. (2014) Yes -
10 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.484G>A p.Ala162Thr missense_variant Unknown - Unknown 24671236 Kova J , et al. (2014)
c.245_264del p.Pro82HisfsTer12 frameshift_variant Familial Paternal Simplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.332A>C;c.227A>C p.Glu111Ala;p.Glu76Ala missense_variant - - - 25201284 Gabriele S , et al. (2014)
c.-7C>T - 5_prime_UTR_variant - - - 24671236 Kova J , et al. (2014)
c.332C>A p.Ala111Glu missense_variant - - - 15386471 Junaid MA , et al. (2004)
c.332C>A;c.227A>C p.Ala111Glu missense_variant - - - 24671236 Kova J , et al. (2014)
c.332C>A;c.227A>C p.Ala111Glu missense_variant - - - 16352396 Politi P , et al. (2005)
SFARI Gene score
2

Strong Candidate

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

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

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2014
4
icon
4

Decreased from 4 to 4

Description

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

Reports Added
[The GLO1 C332 (Ala111) allele confers autism vulnerability: family-based genetic association and functional correlates.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A polymorphism was identified by 2D gel electrophoresis comparing autism brain to control: 4/8 cases and 2/3 controls homozygous for acidic form of GLO1 protein. In 7/8 original cases the A allele is present versus 5/9 controls. The protein variant was determined to be the result of common cSNP, and thus followed-up by case-control analysis in AGRE patients versus complicated combination of control brains and lymphoblastoid cells from Utah families. A significant enrichment of the A allele was observed in cases versus controls (p < 0.0001), and a 40% reduction in GLO1 activity in cases (n=8) versus normal controls (n=4) was observed. Two genetic studies larger than the initial proteomics work failed to see an association between common variants and autism. A third failed to find evidence of case-control differences or increased frequency of A allele in cases but paradoxically found evidence for increased transmission of A allele to unaffected sibs in a family based study (TDT and FBAT P < 0.00001). Expression levels are reduced relative to controls in depressed individuals in depressed state. Very nice molecular work from mouse supports a role of GLO1 in modulation of anxiety (Junaid MA et al.).

Reports Added
[Glyoxalase I polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity--implications for autism.2011] [Weak association of glyoxalase 1 (GLO1) variants with autism spectrum disorder.2014]
Krishnan Probability Score

Score 0.52544080564356

Ranking 1618/25841 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 0.0002206887340657

Ranking 12661/18225 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 0.82527653712125

Ranking 2731/18665 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
Larsen Cumulative Evidence Score

Score 27.5

Ranking 77/461 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.
Original Source
Zhang D Score

Score -0.84630700316989

Ranking 20729/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ASB12 ankyrin repeat and SOCS box containing 12 Human Protein Binding 142689 Q8WXK4
IGBP1 Immunoglobulin-binding protein 1 Human Protein Binding 3476 P78318
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