Human Gene Module / Chromosome 2 / ZNF804A

ZNF804AZinc finger protein 804A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 16
Rare Variants / Common Variants
10 / 9
Aliases
ZNF804A, C2orf10
Associated Syndromes
-
Chromosome Band
2q32.1
Associated Disorders
BPD
Relevance to Autism

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012).

Molecular Function

ZNF804A has been shown to associate with schizophrenia and bipolar disorder in multiple genetic association studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZNF804A (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Identification of loci associated with schizophrenia by genome-wide association and follow-up O'Donovan MC , et al. (2008) No BPD
2 Positive Association Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample Riley B , et al. (2009) No -
3 Positive Association Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder Williams HJ , et al. (2010) No BPD
4 Support Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries Talkowski ME , et al. (2012) No -
5 Support Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways Griswold AJ , et al. (2012) Yes -
6 Primary Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism Anitha A , et al. (2014) Yes -
7 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
8 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
9 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
10 Recent Recommendation Psychosis Risk Candidate ZNF804A Localizes to Synapses and Regulates Neurite Formation and Dendritic Spine Structure Deans PJ , et al. (2016) No -
11 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
12 Support Convergent Evidence That ZNF804A Is a Regulator of Pre-messenger RNA Processing and Gene Expression Chapman RM , et al. (2019) No -
13 Positive Association A promoter variant in ZNF804A decreasing its expression increases the risk of autism spectrum disorder in the Han Chinese population Zhang L , et al. (2019) Yes -
14 Support Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder Schmitz-Abe K et al. (2020) Yes -
15 Support - Dong F et al. (2021) No -
16 Support - Zhou X et al. (2022) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - Unknown 24866414 Anitha A , et al. (2014)
- - copy_number_loss De novo - Unknown 24866414 Anitha A , et al. (2014)
- - copy_number_gain Familial - Unknown 24866414 Anitha A , et al. (2014)
- - translocation Familial Paternal Simplex 22521361 Talkowski ME , et al. (2012)
- - copy_number_gain Familial Paternal Multiplex 22543975 Griswold AJ , et al. (2012)
c.75C>T p.Phe25%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Both parents Simplex 32820185 Schmitz-Abe K et al. (2020)
c.2626A>C p.Arg876%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.613C>G p.Gln205Glu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.346C>T p.Arg116Cys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
Common Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.111+13880A>G - intron_variant - - - 19844207 Riley B , et al. (2009)
c.111+19311C>G - intron_variant - - - 19844207 Riley B , et al. (2009)
c.256-19902A>C - intron_variant - - - 19844207 Riley B , et al. (2009)
c.111+69783T>C T intron_variant - - - 19844207 Riley B , et al. (2009)
c.-1646T>C - 2_KB_upstream_variant - - - 30670685 Zhang L , et al. (2019)
c.112-90368A>T - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.256-31514A>G G/A intron_variant - - - 24866414 Anitha A , et al. (2014)
c.256-19902A>C - intron_variant - - - 20368704 Williams HJ , et al. (2010)
c.256-19902A>C - intron_variant - - - 18677311 O'Donovan MC , et al. (2008)
SFARI Gene score
2

Strong Candidate

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012). A case-control association analysis of 854 ASD cases and 926 controls from the Han Chinese population in Zhang et al., 2019 found that the ZNF804A variant rs10497655 was significantly association with ASD (P = 0.007851); furthermore, it was shown that this variant had a significant effect on ZNF804A expression, with fetal brain samples from individuals homozygous for the T risk allele exhibiting reduced ZNF804A expression. Copy number variants affecting ZNF804A have been observed in ASD cases in Griswold et al., 2012 and Anitha et al., 2012, and potentially damaging de novo missense variants in ZNF804A were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). SNPs in the ZNF804A gene have been shown to strongly associate with schizophrenia and bipolar disorder in multiple studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

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

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012). A case-control association analysis of 854 ASD cases and 926 controls from the Han Chinese population in Zhang et al., 2019 found that the ZNF804A variant rs10497655 was significantly association with ASD (P = 0.007851); furthermore, it was shown that this variant had a significant effect on ZNF804A expression, with fetal brain samples from individuals homozygous for the T risk allele exhibiting reduced ZNF804A expression. Copy number variants affecting ZNF804A have been observed in ASD cases in Griswold et al., 2012 and Anitha et al., 2012, and potentially damaging de novo missense variants in ZNF804A were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). SNPs in the ZNF804A gene have been shown to strongly associate with schizophrenia and bipolar disorder in multiple studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

Reports Added
[Schizophrenia risk ZNF804A interacts with its associated proteins to modulate dendritic morphology and synaptic development2021]
7/1/2020
2
icon
2

Score remained at 2

Description

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012). A case-control association analysis of 854 ASD cases and 926 controls from the Han Chinese population in Zhang et al., 2019 found that the ZNF804A variant rs10497655 was significantly association with ASD (P = 0.007851); furthermore, it was shown that this variant had a significant effect on ZNF804A expression, with fetal brain samples from individuals homozygous for the T risk allele exhibiting reduced ZNF804A expression. Copy number variants affecting ZNF804A have been observed in ASD cases in Griswold et al., 2012 and Anitha et al., 2012, and potentially damaging de novo missense variants in ZNF804A were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). SNPs in the ZNF804A gene have been shown to strongly associate with schizophrenia and bipolar disorder in multiple studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

Reports Added
[Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012). A case-control association analysis of 854 ASD cases and 926 controls from the Han Chinese population in Zhang et al., 2019 found that the ZNF804A variant rs10497655 was significantly association with ASD (P = 0.007851); furthermore, it was shown that this variant had a significant effect on ZNF804A expression, with fetal brain samples from individuals homozygous for the T risk allele exhibiting reduced ZNF804A expression. Copy number variants affecting ZNF804A have been observed in ASD cases in Griswold et al., 2012 and Anitha et al., 2012, and potentially damaging de novo missense variants in ZNF804A were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). SNPs in the ZNF804A gene have been shown to strongly associate with schizophrenia and bipolar disorder in multiple studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

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

Decreased from 3 to 3

Description

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012). A case-control association analysis of 854 ASD cases and 926 controls from the Han Chinese population in Zhang et al., 2019 found that the ZNF804A variant rs10497655 was significantly association with ASD (P = 0.007851); furthermore, it was shown that this variant had a significant effect on ZNF804A expression, with fetal brain samples from individuals homozygous for the T risk allele exhibiting reduced ZNF804A expression. Copy number variants affecting ZNF804A have been observed in ASD cases in Griswold et al., 2012 and Anitha et al., 2012, and potentially damaging de novo missense variants in ZNF804A were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). SNPs in the ZNF804A gene have been shown to strongly associate with schizophrenia and bipolar disorder in multiple studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

Reports Added
[Convergent Evidence That ZNF804A Is a Regulator of Pre-messenger RNA Processing and Gene Expression.2019] [A promoter variant in ZNF804A decreasing its expression increases the risk of autism spectrum disorder in the Han Chinese population.2019]
10/1/2017
icon
3

Increased from to 3

Description

A SNP located in intron 2 of the ZNF804A gene (rs7603001) was found to be nominally associated with autism (p=0.018); this association was stronger (p=0.008) in the families of individuals with autism who were verbally deficient (n=761 families). In this same report, ZNF804A expression was found to be reduced in the anterior cingulate gyrus (ACG) of individuals with autism (p=0.009) (Anitha et al., 2012). Copy number variants affecting ZNF804A have been observed in ASD cases in Griswold et al., 2012 and Anitha et al., 2012, and potentially damaging de novo missense variants in ZNF804A were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). SNPs in the ZNF804A gene have been shown to strongly associate with schizophrenia and bipolar disorder in multiple studies (O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011).

Krishnan Probability Score

Score 0.52916521026098

Ranking 1570/25841 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 0.82743629107384

Ranking 3768/18225 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
Iossifov Probability Score

Score 0.884

Ranking 160/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.74305166133346

Ranking 1488/18665 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 3

Ranking 370/461 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 0.22628150971269

Ranking 3836/20870 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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