Human Gene Module / Chromosome 17 / SLC6A4

SLC6A4solute carrier family 6 (neurotransmitter transporter, serotonin), member 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
16 / 26
Rare Variants / Common Variants
26 / 23
Aliases
SLC6A4, HTT,  5HTT,  OCD1,  SERT,  5-HTT,  hSERT
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
17q11.2
Associated Disorders
ID, EPS
Relevance to Autism

Several studies have found genetic association between the SLC6A4 gene and autism in AGRE, CPEA, French-Caucasian, Portuguese and several mixed US population cohorts. However, several other studies found no genetic association between the SLC6A4 gene and autism in AGRE, SARC, US and Chinese Han population cohorts. Separately, genetic association has been found between the SLC6A4 gene and pervasive developmental disorder (PDD) in a Dutch population cohort. In addition, rare mutations in the SLC6A4 gene have been identified in individuals with ASD (Neale et al., 2012).

Molecular Function

The encoded protein has serotonin transporter activity, serotonin:sodium symport er activity.

Reports related to SLC6A4 (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Kim SJ , et al. (2002) Yes -
2 Highly Cited Serotonin transporter genetic variation and the response of the human amygdala. Hariri AR , et al. (2002) No -
3 Positive Association Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia. Anderson GM , et al. (2002) Yes -
4 Positive Association Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism. Coutinho AM , et al. (2004) Yes -
5 Negative Association Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism. McCauley JL , et al. (2004) Yes -
6 Positive Association Serotonin transporter intron 2 polymorphism associated with rigid-compulsive behaviors in Dutch individuals with pervasive developmental disorder. Mulder EJ , et al. (2005) No -
7 Negative Association Lack of evidence for association between the serotonin transporter gene (SLC6A4) polymorphisms and autism in the Chinese trios. Wu S , et al. (2005) Yes -
8 Positive Association Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Sutcliffe JS , et al. (2005) Yes -
9 Positive Association Autism and the serotonin transporter: the long and short of it. Devlin B , et al. (2005) Yes -
10 Recent Recommendation The molecular genetic architecture of human personality: beyond self-report questionnaires. Ebstein RP (2006) No -
11 Negative Association Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism. Ramoz N , et al. (2006) Yes -
12 Recent Recommendation Social approach in genetically engineered mouse lines relevant to autism. Moy SS , et al. (2008) No -
13 Recent Recommendation Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior. Page DT , et al. (2009) No -
14 Support Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants. Adamsen D , et al. (2010) Yes -
15 Support Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Veenstra-VanderWeele J , et al. (2012) No -
16 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
17 Positive Association Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder. Moya PR , et al. (2013) No -
18 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut... Koshimizu E , et al. (2013) Yes ID, epilepsy
19 Negative Association Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population. Ro M , et al. (2013) Yes -
20 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
21 Positive Association Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism. Nyffeler J , et al. (2014) Yes -
22 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
23 Support Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress. Hecht PM , et al. (2016) No -
24 Support The influence of 5-HTTLPR transporter genotype on amygdala-subgenual anterior cingulate cortex connectivity in autism spectrum disorder. Velasquez F , et al. (2017) No -
25 Negative Association Association Between 5-HTTLPR Polymorphism and the Risk of Autism: A Meta-Analysis Based on Case-Control Studies. Wang H , et al. (2019) Yes -
26 Primary Evidence of linkage between the serotonin transporter and autistic disorder. Cook EH Jr , et al. (1997) Yes -
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
IVS1a-25G>A - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
IVS1a-47G>C - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-124+28G>A - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-221+20C>T - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1076+83C>T - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1205-33C>T - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-221+133G>A - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.*328A>G - 3_prime_UTR_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-149C>A - 5_prime_UTR_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-324C>T - 2KB_upstream_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-482T>C - 2KB_upstream_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.167G>C p.Gly56Ala missense_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.201C>T p.Thr67= synonymous_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1273A>G p.Ile425Val missense_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1393T>C p.Phe465Leu missense_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1648C>G p.Leu550Val missense_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1815A>C p.Lys605Asn missense_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-859A>C;c.-733A>C - 2KB_upstream_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-1089A>T;c.-963A>T - 2KB_upstream_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.-2192G>A;c.-2066G>A - 5KB_upstream_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1726A>G p.Ile576Val missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.732G>C p.Gly244= synonymous_variant De novo NA Simplex 22495311 Neale BM , et al. (2012)
c.878C>T p.Ser293Phe missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.167G>C p.Gly56Ala missense_variant Familial Maternal Unknown 21183371 Adamsen D , et al. (2010)
- Promoter indel, 2KB_upstream_variant Familial Both parents Unknown 21183371 Adamsen D , et al. (2010)
c.1273A>G p.Ile425Val missense_variant Familial Paternal Multi-generational 23630162 Moya PR , et al. (2013)
Common Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.343+38_343+46GGGTGGGCT[9][10][12][1];c.469+38_469+46GGGTGGGCT[9][10][12][1] - microsatellite, intron_variant - - - 11920155 Kim SJ , et al. (2002)
c.343+38_343+46GGGTGGGCT[9][10][12][1];c.469+38_469+46GGGTGGGCT[9][10][12][1] - microsatellite, intron_variant - - - 15635668 Mulder EJ , et al. (2005)
c.343+38_343+46GGGTGGGCT[9][10][12][1];c.469+38_469+46GGGTGGGCT[9][10][12][1] - microsatellite, intron_variant - - - 15094787 Coutinho AM , et al. (2004)
N/A N/A indel, 2KB_upstream_variant - - - 11920155 Kim SJ , et al. (2002)
N/A N/A indel, 2KB_upstream_variant - - - 9152989 Cook EH Jr , et al. (1997)
N/A N/A indel, 2KB_upstream_variant - - - 16103890 Devlin B , et al. (2005)
c.-185C>A;c.-59C>A - 5_prime_UTR_variant - - - 11920155 Kim SJ , et al. (2002)
N/A N/A indel, 2KB_upstream_variant - - - 25408912 Nyffeler J , et al. (2014)
N/A N/A indel, 2KB_upstream_variant - - - 12232775 Anderson GM , et al. (2002)
N/A N/A indel, 2KB_upstream_variant - - - 15094787 Coutinho AM , et al. (2004)
N/A N/A indel, 2KB_upstream_variant - - - 15108191 McCauley JL , et al. (2004)
c.344-965G>A;c.470-965G>A - intron_variant - - - 11920155 Kim SJ , et al. (2002)
N/A N/A indel, 2KB_upstream_variant - - - 15995945 Sutcliffe JS , et al. (2005)
c.1205-90G>A;c.1331-90G>A A/G intron_variant - - - 24192574 Ro M , et al. (2013)
c.-220-824T>A;c.-94-824T>A - intron_variant - - - 11920155 Kim SJ , et al. (2002)
c.-220-881C>T;c.-94-881C>T - intron_variant - - - 11920155 Kim SJ , et al. (2002)
N/A Intron 7 microsatellite, intron_variant - - - 11920155 Kim SJ , et al. (2002)
c.-220-1732C>T;c.-94-1732C>T - intron_variant - - - 11920155 Kim SJ , et al. (2002)
c.-221+1171T>C;c.-95+1171T>C - intron_variant - - - 11920155 Kim SJ , et al. (2002)
c.-1936A>G;c.-1810A>G - 2KB_upstream_variant - - - 23630162 Moya PR , et al. (2013)
c.-221+1176A>T;c.-95+1176A>T - intron_variant - - - 16616719 Ramoz N , et al. (2006)
c.838-155G>A;c.964-155G>A - intron_variant - - - 15108191 McCauley JL , et al. (2004)
c.838-155G>A;c.964-155G>A - intron_variant - - - 15995945 Sutcliffe JS , et al. (2005)
SFARI Gene score
3

Suggestive Evidence

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

Score Delta: Score remained at 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

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

Decreased from 4 to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

1/1/2017
4
icon
4

Decreased from 4 to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

4/1/2016
4
icon
4

Decreased from 4 to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

Reports Added
[Evidence of linkage between the serotonin transporter and autistic disorder.1997] [Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.2002] [Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia.2002] [Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism.2004] [Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism.2004] [Lack of evidence for association between the serotonin transporter gene (SLC6A4) polymorphisms and autism in the Chinese trios.2005] [Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.2005] [Autism and the serotonin transporter: the long and short of it.2005] [Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism.2006] [Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population.2013] [Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism.2014] [Serotonin transporter intron 2 polymorphism associated with rigid-compulsive behaviors in Dutch individuals with pervasive developmental disorder.2005] [Serotonin transporter genetic variation and the response of the human amygdala.2002] [The molecular genetic architecture of human personality: beyond self-report questionnaires.2006] [Social approach in genetically engineered mouse lines relevant to autism.2008] [Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.2009] [Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder.2013] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress.2016]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

Reports Added
[Evidence of linkage between the serotonin transporter and autistic disorder.1997] [Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.2002] [Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia.2002] [Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism.2004] [Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism.2004] [Lack of evidence for association between the serotonin transporter gene (SLC6A4) polymorphisms and autism in the Chinese trios.2005] [Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.2005] [Autism and the serotonin transporter: the long and short of it.2005] [Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism.2006] [Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population.2013] [Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism.2014] [Serotonin transporter intron 2 polymorphism associated with rigid-compulsive behaviors in Dutch individuals with pervasive developmental disorder.2005] [Serotonin transporter genetic variation and the response of the human amygdala.2002] [The molecular genetic architecture of human personality: beyond self-report questionnaires.2006] [Social approach in genetically engineered mouse lines relevant to autism.2008] [Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.2009] [Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder.2013]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

7/1/2014
No data
icon
4

Increased from No data to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Several gene-based association studies have been carried out, but with mixed results and no true replications. In one family a single functional missense mutation was found to segregate with an OCD phenotype; two affected individuals also had Asperger syndrome.

Krishnan Probability Score

Score 0.49493920513895

Ranking 3328/25841 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 0.85488009451934

Ranking 3584/18225 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 0.93646254031089

Ranking 13204/18665 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 74.5

Ranking 17/461 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 -0.44732062932715

Ranking 18798/20870 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 SLC6A4(1 CNVs)
17q11.2 24 Deletion-Duplication 38  /  103
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
SNCG Gamma-synuclein Human Protein Binding 6623 O76070
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