Human Gene Module / Chromosome 12 / TPH2

TPH2tryptophan hydroxylase 2

Score
6
Not Supported Criteria 6.1
Autism Reports / Total Reports
7 / 12
Rare Variants / Common Variants
2 / 8
Aliases
TPH2, NTPH,  FLJ37295
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
12q21.1
Associated Disorders
-
Relevance to Autism

Genetic association has been found between the TPH2 gene and autism in a Caucasian (from US and Italy) population cohort (Coon et al., 2005). However, other studies have found no genetic association between the TPH2 gene and autism in Italian, Caucasian-American and other population cohorts. Separately, genetic association has been found between the TPH2 gene and unipolar major depression in a US population cohort.

Molecular Function

The encoded protein has tryptophan 5-monooxygenase activity.

Reports related to TPH2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Tryptophan hydroxylase-2 controls brain serotonin synthesis. Zhang X , et al. (2004) No -
2 Highly Cited Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Zhang X , et al. (2005) No -
3 Primary Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). Coon H , et al. (2005) Yes -
4 Negative Association No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects. Delorme R , et al. (2006) Yes OCD, Affective disorders
5 Recent Recommendation Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Herrmann MJ , et al. (2006) No -
6 Recent Recommendation Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic-pituitary-adrenal axis function and in vitro gene expr... Chen GL , et al. (2006) No -
7 Recent Recommendation Functional domains of human tryptophan hydroxylase 2 (hTPH2). Carkaci-Salli N , et al. (2006) No -
8 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 -
9 Negative Association A detailed association analysis between the tryptophan hydroxylase 2 (TPH2) gene and autism spectrum disorders in a Japanese population. Egawa J , et al. (2012) Yes -
10 Positive Association Association with tryptophan hydroxylase 2 gene polymorphisms and autism spectrum disorders in Korean families. Yang SY , et al. (2012) Yes -
11 Positive Association Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indi... Singh AS , et al. (2013) Yes -
12 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
T>C - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.674G>A p.Arg225Gln missense_variant Familial Paternal - 22361444 Egawa J , et al. (2012)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-844G>T T/G 2KB_upstream_variant - - - 22698779 Yang SY , et al. (2012)
c.-844G>T G/T 2KB_upstream_variant - - - 23628433 Singh AS , et al. (2013)
c.1322G>A p.Arg441His missense_variant - - - 15629698 Zhang X , et al. (2005)
c.540+162A>T;c.558+162A>T - intron_variant - - - 15768392 Coon H , et al. (2005)
c.936A>G;c.954A>G p.(=) synonymous_variant - - - 22698779 Yang SY , et al. (2012)
c.106-291G>T;c.106-273G>T T>G intron_variant - - - 15768392 Coon H , et al. (2005)
c.540+1607G>T;c.558+1607G>T T/G intron_variant - - - 22361444 Egawa J , et al. (2012)
c.540+1607G>T;c.558+1607G>T G/T intron_variant - - - 22698779 Yang SY , et al. (2012)
SFARI Gene score
6

Not Supported

6

Score Delta: Score remained at 6.1

6

Not Supported

See all Category 6 Genes

The weight of the evidence argues against a role in autism.

10/1/2016
6
icon
6

Score remained at 6

Description

Single positive association (PMID: 15768392), followed by 3 negative associations (PMIDs: 16581035, 16958027, 17346350). Weight of evidence suggests first study was a false-positive.

7/1/2014
No data
icon
6

Increased from No data to 6

Description

Single positive association (PMID: 15768392), followed by 3 negative associations (PMIDs: 16581035, 16958027, 17346350). Weight of evidence suggests first study was a false-positive.

4/1/2014
No data
icon
6

Increased from No data to 6

Description

Single positive association (PMID: 15768392), followed by 3 negative associations (PMIDs: 16581035, 16958027, 17346350). Weight of evidence suggests first study was a false-positive.

Krishnan Probability Score

Score 0.49338701132522

Ranking 4182/25841 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 0.69691187625486

Ranking 4497/18225 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 0.92882335393741

Ranking 11011/18665 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).
Larsen Cumulative Evidence Score

Score 9

Ranking 214/461 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.
Zhang D Score

Score -0.36933334497881

Ranking 18036/20870 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.
CNVs associated with TPH2(1 CNVs)
12q21.1 10 Deletion-Duplication 17  /  66
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