SLC6A4solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
Autism Reports / Total Reports
18 / 31Rare Variants / Common Variants
28 / 23Aliases
SLC6A4, HTT, 5HTT, OCD1, SERT, 5-HTT, hSERTAssociated Syndromes
-Chromosome Band
17q11.2Associated Disorders
ID, EPSRelevance 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.
External Links
SFARI Genomic Platforms
Reports related to SLC6A4 (31 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 autism spectrum disorder | 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 | Support | - | Thorne BN et al. (2022) | No | - |
27 | Support | - | De Gregorio R et al. (2022) | No | - |
28 | Support | - | Shoji H et al. (2023) | No | Anxiety |
29 | Support | - | Hu C et al. (2023) | Yes | - |
30 | Support | - | Sheth F et al. (2023) | Yes | DD, ID |
31 | Primary | Evidence of linkage between the serotonin transporter and autistic disorder | Cook EH Jr , et al. (1997) | Yes | - |
Rare Variants (28)
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 | - | - | 25363760 | De Rubeis S , et al. (2014) | |
c.1534G>C | p.Val512Leu | missense_variant | Familial | Paternal | - | 37007974 | Hu C et al. (2023) | |
c.732G>C | p.Gly244= | synonymous_variant | De novo | - | 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.1745dup | p.Thr583AsnfsTer23 | frameshift_variant | Familial | Maternal | Simplex | 37543562 | Sheth F et al. (2023) | |
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
Strong Candidate
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 2
criteria met
See SFARI Gene'scoring criteriaWe 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.
4/1/2022
Decreased from 3 to 2
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.
10/1/2019
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
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
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
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
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
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
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
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]
ExAC Score
Score 0.85488009451934
Ranking 3584/18225 scored genes
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Sanders TADA Score
Score 0.93646254031089
Ranking 13204/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 74.5
Ranking 17/461 scored genes
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Zhang D Score
Score -0.44732062932715
Ranking 18798/20870 scored genes
[Show Scoring Methodology]
CNVs associated with SLC6A4(1 CNVs)
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17q11.2 | 29 | Deletion-Duplication | 44 / 116 |
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
---|---|---|---|---|---|
SNCG | Gamma-synuclein | Human | Protein Binding | 6623 | O76070 |