Human Gene Module / Chromosome 17 / ITGB3

ITGB3integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 22
Rare Variants / Common Variants
9 / 6
Aliases
ITGB3, CD61,  GP3A, GPIIIa
Associated Syndromes
-
Chromosome Band
17q21.32
Associated Disorders
ADHD
Relevance to Autism

Several studies have found genetic association between the ITGB3 gene and autism in a number of population cohorts, and a rare mutation in the ITGB3 gene has been identified in an individual with ASD (ORoak et al., 2012).

Molecular Function

The encoded protein is the integrin beta chain beta 3 that participates in cell adhesions and cell-surface mediated signalling.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ITGB3 (22 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study Feng D , et al. (1999) No -
2 Positive Association Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin Weiss LA , et al. (2004) No -
3 Primary Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility Weiss LA , et al. (2006) Yes -
4 Positive Association Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels Coutinho AM , et al. (2007) Yes -
5 Positive Association Multifactor dimensionality reduction-phenomics: a novel method to capture genetic heterogeneity with use of phenotypic variables Mei H , et al. (2007) Yes -
6 Recent Recommendation A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia Ghevaert C , et al. (2007) No -
7 Recent Recommendation The Foxc2 transcription factor regulates angiogenesis via induction of integrin beta3 expression Hayashi H , et al. (2008) No -
8 Positive Association Association and gene-gene interaction of SLC6A4 and ITGB3 in autism Ma DQ , et al. (2009) Yes -
9 Recent Recommendation AlphaIIbbeta3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function Jallu V , et al. (2009) No -
10 Positive Association Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes Napolioni V , et al. (2010) Yes -
11 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
12 Positive Association Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population Singh AS , et al. (2013) Yes -
13 Positive Association Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis Namjou B , et al. (2014) No -
14 Recent Recommendation The Gain-of-Function Integrin ?3 Pro33 Variant Alters the Serotonin System in the Mouse Brain Dohn MR , et al. (2017) Yes ADHD
15 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
16 Support - Alonso-Gonzalez A et al. (2021) Yes -
17 Support - Woodbury-Smith M et al. (2022) Yes -
18 Support - Lopuch AJ et al. (2022) Yes -
19 Support - Zhou X et al. (2022) Yes -
20 Support - Jaudon F et al. (2022) No -
21 Support - Handwerk CJ et al. (2023) No -
22 Support - Celora L et al. (2023) No -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.20C>T p.Pro7Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1664T>C p.Val555Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1469C>T p.Pro490Leu synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.72C>T p.Gly24%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1133G>A p.Arg378His missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1700_1701del p.Gln567LeufsTer9 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.615-1G>C - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.62C>T p.Ala21Val missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.206dup p.Asn69LysfsTer6 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- p.Leu33Pro missense_variant - - - 29038237 Dohn MR , et al. (2017)
T p.Leu33Pro missense_variant - - - 16724005 Weiss LA , et al. (2006)
c.*1016T>A N/A 3_prime_UTR_variant - - - 19588468 Ma DQ , et al. (2009)
c.1914-267G>T - intron_variant - - - 21102624 Napolioni V , et al. (2010)
c.176T>C p.Leu59Pro missense_variant - - - 23628433 Singh AS , et al. (2013)
c.80-3764T>C Minor allele, C intron_variant - - - 25477900 Namjou B , et al. (2014)
SFARI Gene score
2

Strong Candidate

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

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.

1/1/2021
2
icon
2

Score remained at 2

Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

Reports Added
[The Gain-of-Function Integrin 3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.2017] [Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin.2004]
1/1/2015
3
icon
3

Decreased from 3 to 3

Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

Reports Added
[Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos...2014]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

ITGB3 has been associated with both serotonin levels and SLC6A4 levels (PMID: 16724005), and an interaction between ITGB3 and SLC6A4 has been observed (PMIDs: 17203304, 17999363). Both sex-specific effects and influence of family history have been noted. For association studies, there have been inconsistent findings (no single SNP seems to be consistently replicated; PMIDs: 21182210, 21102624, 19588468, 16721604).

Krishnan Probability Score

Score 0.49268859336471

Ranking 4442/25841 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 0.14169954464492

Ranking 7458/18225 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 0.76520828640092

Ranking 1717/18665 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 8

Ranking 227/461 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 -0.15433152369413

Ranking 14261/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
c-SRC v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog Human Protein Modification 6714 P41240
CD31 platelet/endothelial cell adhesion molecule 1 Mouse Protein Binding 18613 Q08481
CD36 CD36 molecule (thrombospondin receptor) Human Protein Binding 948 P16671
CIB1 calcium and integrin binding 1 (calmyrin) Human Protein Binding 10519 Q99828
COL1A2 collagen, type I, alpha 2 Human Protein Binding 1278 P08123
DOK1 docking protein 1, 62kDa (downstream of tyrosine kinase 1) Human Protein Binding 1796 Q99704
FAK PTK2 protein tyrosine kinase 2 Chicken Protein Binding 396416 Q00944
FBLN2 fibulin 2 Mouse Protein Binding 14115 P37889
FGA fibrinogen alpha chain Human Protein Binding 2243 P02671
FOXC2 forkhead box C2 Mouse DNA Binding 14234 Q61850
ITGA2B integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) Human Protein Binding 3674 P08514
MIR30 microRNA 30a Human DNA Binding 407029 N/A: miRNA
MIRLET7A1 microRNA let-7a-1 Human DNA Binding 406881 N/A: miRNA
NRIF3 integrin beta 3 binding protein (beta3-endonexin) Human Protein Binding 23421 Q13352
P2RY2 purinergic receptor P2Y, G-protein coupled, 2 Human Protein Binding 5029 P41231
PDGFRA platelet-derived growth factor receptor, alpha polypeptide Human Protein Binding 5156 P16234
PDGFRB platelet-derived growth factor receptor, beta polypeptide Human Protein Binding 5159 P09619
TGM2 transglutaminase 2 Human Protein Binding 7052 P21980
THBS1 thrombospondin 1 Human Protein Binding 7057 P07996
THY1 Thy-1 cell surface antigen Human Protein Binding 7070 P04216
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