Human Gene Module / Chromosome 15 / GABRG3

GABRG3gamma-aminobutyric acid type A receptor gamma3 subunit

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 9
Rare Variants / Common Variants
5 / 4
Aliases
-
Associated Syndromes
-
Genetic Category
Genetic Association
Chromosome Band
15q12
Associated Disorders
-
Relevance to Autism

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Molecular Function

This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. The protein encoded by this gene is a gamma subunit, which contains the benzodiazepine binding site.

Reports related to GABRG3 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. Menold MM , et al. (2002) Yes -
2 Negative Association A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. McCauley JL , et al. (2004) Yes -
3 Negative Association Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Ma DQ , et al. (2005) Yes -
4 Support An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as ris... Ashley-Koch AE , et al. (2006) No -
5 Negative Association No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population. Tochigi M , et al. (2007) Yes -
6 Negative Association Polymorphisms of candidate genes in Slovak autistic patients. Kelemenova S , et al. (2010) Yes -
7 Positive Association GABAA receptor subunit gene polymorphisms predict symptom-based and developmental deficits in Chinese Han children and adolescents with autistic sp... Yang S , et al. (2017) Yes -
8 Negative Association Meta-Analysis of the Association between GABA Receptor Polymorphisms and Autism Spectrum Disorder (ASD). Mahdavi M , et al. (2018) Yes -
9 Positive Association Association study and mutation sequencing of genes on chromosome 15q11-q13 identified GABRG3 as a susceptibility gene for autism in Chinese Han pop... Wang L , et al. (2018) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.697G>A p.Val233Met missense_variant De novo NA - 30108208 Wang L , et al. (2018)
c.1093C>T p.Pro365Ser missense_variant De novo NA - 30108208 Wang L , et al. (2018)
c.697G>A p.Val233Met missense_variant Familial Maternal - 30108208 Wang L , et al. (2018)
c.697G>A p.Val233Met missense_variant Familial Paternal - 30108208 Wang L , et al. (2018)
c.1093C>T p.Pro365Ser missense_variant Familial Paternal - 30108208 Wang L , et al. (2018)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.203-18722C>A - intron_variant - - - 30108208 Wang L , et al. (2018)
c.574+81T>C - intron_variant - - - 12092907 Menold MM , et al. (2002)
c.271-147049A>T - intron_variant - - - 28607477 Yang S , et al. (2017)
c.507T>C p.(=) synonymous_variant - - - 12092907 Menold MM , et al. (2002)
SFARI Gene score
2

Strong Candidate

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Score Delta: Score remained at 3

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
3

Increased from to 3

Description

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Krishnan Probability Score

Score 0.5699058242114

Ranking 990/25841 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 0.99367984420864

Ranking 1622/18225 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 0.94182427251601

Ranking 15076/18665 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).
Zhang D Score

Score 0.28450435899971

Ranking 2963/20870 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.
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We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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