Identity
HGNC
LOCATION
17q11.2
IMAGE
LEGEND
Figure 1. Genomic location of SLC6A4 (Chromosome 17 - NC_000017.11 Reference GRCh38.p12 Primary Assembly)
IMAGE
LEGEND
Figure 2. Chromosomal Location of SLC6A4. Cytogenetic Location: 17q11.2, which is the long (q) arm of chromosome 17 at position 11.2 (U.S. National Library of Medicine)
LOCUSID
ALIAS
5-HTT,5-HTTLPR,5HTT,HTT,OCD1,SERT,SERT1,hSERT
FUSION GENES
Abstract
The SLC6A4 gene encodes a sodium-dependent serotonin reuptake protein delivering the neurotransmitter serotonin from the synaptic cleft back to the presynaptic end. Its main function is to abort the activity of serotonin and forward it to neurotransmitter pool for recycling. The psychomotor stimulant drugs mainly amphetamines and cocaine act on this transmembrane protein which is a member of the sodium: neurotransmitter symporter family. SLC6A4 gene polymorphisms affect the rate of serotonin reuptake and play an important role in pathogenesis of various illnesses like Sudden infant death syndrome, aggressive behaviour in Alzheimer patients, Seasonal affective disorder, Major depressive Disorder and Obsessive-compulsive disorder.
DNA/RNA
Note
The SLC6A4 gene is 41,684 bp long (according to UCSC, GRCh38/hg38), located on the plus strand and spans 15 exons (NCBI Homo sapiens Annotation Release 109).
Figure 3. Numbers and illustrative sizes of exons of human SLC6A4. (https:\\www.atlasgeneticsoncology.org)
Transcription
The gene has 5 transcripts (Table 1)
Table 1. Transcripts of human SLC6A4 gene (Ensemble, GRCh38.p12).
| Name | Transcript ID | bp | Protein (aa) | Biotype |
| SLC6A4-201 | ENST00000261707.7 | 6604 | 630 aa | Protein coding |
| SLC6A4-202 | ENST00000394821.2 | 2160 | 618 aa | Protein coding |
| SLC6A4-203 | ENST00000401766.6 | 6543 | 630 aa | Protein coding |
| SLC6A4-204 | ENST00000578609.1 | 566 | No protein | Retained intron |
| SLC6A4-205 | ENST00000579221.5 | 1069 | 72 aa | Nonsense mediated decay |
Table 1. Transcripts of human SLC6A4 gene (Ensemble, GRCh38.p12).
Proteins
Note
SLC6A4 gene encodes a serotonin transporter protein (5-HTT) of 70,320 Dalton and composed of 630 amino acids (Figure 4) (Ramamoorthy et al., 1993). The protein belongs to family of neurotransmitter/sodium transporter (NSS). NSS family also includes dopamine, glycine and γ -aminobutyric acid (GABA) transporters (Chen et al., 2004). The members of this family have 12 transmembrane domains and intracellular N and C terminal regions (Yamashita et al., 2005). The large extracellular structure (EL) between TM3 and TM4 is modified by N-linked glycosylation in all eukaryotic NSS proteins and the number of N-linked glycosylation sites can vary from carrier to carrier. The consensus sequence for N-linked glycosylation is N-X-S/T (the amide nitrogen glycan binding region in the asparagine side chain and X is any amino acid except proline) (Mitra et al., 2006). The EL2 of the 5-HTT protein has two glycosylation sites carrying glycan (Tate and Blakely,. 1994). Mutations in the glycosylation sites of 5-HTT and other NSS proteins generally cause problems in the transport of neurotransmitter proteins such as serotonin at the cell surface (Tate and Blakely,.1994 ; Olivares et al., 1995; Melikian et al., 1996; Li et al., 2004).
Figure 4. Structure of human Solute carrier family 6 member 4. X-ray structure of the ts3 human serotonin transporter complexed with paroxetine (selective serotonin re-uptake inhibitor) at the central site (PDB ID: 5I6X) (https://www.rcsb.org).
Expression
SLC6A4 gene is most commonly expressed in gastrointestinal tract, female tissues, and lung. It is less expressed in muscle, skin, endocrine, male, and female tissues (http://www.proteinatlas.org).
Figure 5. Expression profile of SLC6A4 in different tissues/organs in human. Data were taken from The Human Protein Atlas (http://www.proteinatlas.org) in December, 2018.
Localisation
SLC6A4 is found in various cellular compartments such as cytosol, endosome, plasma membrane, and integral component of plasma membrane, integral component of postsynaptic membrane, integral component of presynaptic membrane, endomembrane system, neuron projection, and serotonergic synapse (Müller et al., 2006; Brenner et al., 2007; Ahmed et al., 2008; Ahmed et al., 2009; Gaudet et al., 2011).
Function
5-HTT protein activity relies on the concentrations of intracellular potassium and extracellular sodium and chloride ions. It also depends on the membrane potential generated by sodium-potassium adenosine triphosphatase for the activity of the 5-HTT protein. The 5-HTT protein binds itself to sodium, serotonin and chloride ions, respectively. Thus, the membrane potential mediates the release of sodium and chloride molecules pre-bound to the 5-HTT protein and the 5-HTT protein passes into the cell. The 5-HTT protein releases serotonin in the cell and binds a potassium ion to itself. 5-HTT is activated by potassium ion and may be out of the cell. Serotonin (5-hydroxytryptamine; 5-HT) is an important neurotransmitter substance in the central and peripheral nervous system. After release of 5-HT into brain synapses, the Na+ and CI-ions-dependent high-affinity serotonin transporter SLC6A4 (also called 5-hydroxytryptamine transporter, 5-HTT, SERT), which is localized in presynaptic neuronal membranes, effectively clears 5-HT from the synaptic space. Thus, the synaptic activity of 5-HT is terminated by 5-HTT and reintroduced into the neurotransmitter pool for re-use. In this way, 5-HTT has an important role in the retrieval of serotonin and the execution of serotonergic function (Gelernter J. Et al., 1998, Catalano M., 1999).
The 5-HTT activity is rapidly regulated by a number of G-protein-linked receptors and protein kinase-associated pathways including protein kinase C (PKC), PRKG1 (protein kinase G, PKG), and p38 mitogen-activated protein kinase (MAPK). The PKC-dependent phosphorylation and down-regulation of the 5-HTT protein is sensitive to extracellular 5-HT and plays a regulatory role in the transport of 5-HT (Ramamoorthy et al., 1998; Ramamoorthy et al., 1999; Zhu et al., 2004; Samuvel et al., 2005; Prasad et al., 2005).
The 5-HTT activity is rapidly regulated by a number of G-protein-linked receptors and protein kinase-associated pathways including protein kinase C (PKC), PRKG1 (protein kinase G, PKG), and p38 mitogen-activated protein kinase (MAPK). The PKC-dependent phosphorylation and down-regulation of the 5-HTT protein is sensitive to extracellular 5-HT and plays a regulatory role in the transport of 5-HT (Ramamoorthy et al., 1998; Ramamoorthy et al., 1999; Zhu et al., 2004; Samuvel et al., 2005; Prasad et al., 2005).
Figure 6. Serotonergic Synapse Pathway Map. Once released from presynaptic axonal terminals, 5-HT binds to receptors, which have been divided into 7 subfamilies on the basis of conserved structures and signalling mechanisms. These families include the ionotropic 5-HT3 receptors and G-protein-coupled 5-HT receptors, the 5-HT1 (Gi /Go -coupled), 5-HT2 (Gq-coupled), 5-HT4/6/7 (Gs-coupled) and 5-HT5 receptors. Presynaptically localized 5-HT1B receptors are thought to be the autoreceptors that suppress excess 5-HT release. 5-HTs actions are terminated by transporter- mediated reuptake into neurons, leading to catabolism by monoamine oxidase. Data were taken from KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg/) in February, 2019.
Figure 7. Pairwise alignment of SLC6A4 gene protein sequences (in distance from human) (HomoloGene, NCBI).
Mutations
Note
Most frequent mutations are located in the 5-HTTLPR of the promoter region of SLC6A4 gene. These mutations lead to the clinical picture of Autism (rs6365, rs28914832, rs140700) (Sutcliffe et al., 2005 ; Landaas et al., 2010 ; Adamsen et al., 2011), Increased rigid-compulsive behaviour in autism (rs28914833, rs28914834) (Sutcliffe et al., 2005; Rao et al., 2017), Obsessive-compulsive disorder (rs25532) (Wendland et al., 2007), Major depressive disorder (rs6354) (Rao et al., 2017), Panic disorder (rs3813034) (Gyawali et al., 2010), Unipolar disorder (Ogilvie et al., 1996), and Pulmonary arterial hypertension (Eddahibi et al., 2003) (Table 2).
Table 2. Solute Carrier Family 6 Member 4 (SLC6A4) related mutations.
| Missense/Nonsense Mutations | ||||||||
| # | Location | Mutation | Protein | Reported Phenotype | Reference | |||
| 1 | Exon 2 | c.10A>G | p.T4A | Enhanced 5-HT transport activity | Parasad et al., 2005 | |||
| 2 | Exon2 | c.167G>C | p.G56A | Autism, association with | Sutcliffe et al., 2005 | |||
| Camarena et al., 2012 | ||||||||
| 3 | chr17:30218213 | c.603G>C | p.K201N | Increased transporter activity | Rasmussen et al., 2009 | |||
| 4 | Exon 4 | c.643G>A | p.E215K | MAPK nonresponsiveness | Parasad et al., 2005 | |||
| 5 | Exon 6 | c.878C>T | p.S293F | Enhanced 5-HT transport activity | Parasad et al., 2005 | |||
| 6 | Exon 7 | c.1016C>T | p.P339L | Reduced uptake activity | Parasad et al., 2005 | |||
| 7 | Exon 8 | c.1084C>A | p.L362M | Enhanced 5-HT transport activity | Parasad et al.i 2005 | |||
| 8 | Exon 9 | c.1273A>C | p.I425L | Autism, association with | Sutcliffe et al., 2005 | |||
| 9 | Exon 9 | c.1273A>G | p.I425V | Obsessive-compulsive disorder,susceptibility, association | Ozaki et al., 2003 | |||
| Moya et al., 2013 | ||||||||
| 10 | Exon 10 | c.1393T>C | p.F465L | Increased rigid-compulsive behavior in autism, association with | Sutcliffe et al., 2005 | |||
| 11 | Exon 12 | c.1648C>G | p.L550V | Increased rigid-compulsive behavior in autism, association with | Sutcliffe et al., 2005 | |||
| Rao et al., 2017 | ||||||||
| 12 | Exon13 | c.1815A>C | p.K605N | MAPK nonresponsiveness | Parasad et al., 2005 | |||
| Rao et al., 2017 | ||||||||
| 13 | Exon 14 | c.1861C>T | p.P621S | MAPK nonresponsiveness | Parasad et al., 2005 | |||
| Splicing Mutation | ||||||||
| 14 | chr17:30216371 | c.838-155G>A | NA | Autism, association with | Sutcliffe et al., 2005 | |||
| Landaas et al., 2010 | ||||||||
| Regulatory Mutation | ||||||||
| 15 | chr17:30237328 | c.-1936G>A | NA | Obsessive-compulsive disorder, association with | Hu et al., 2006 | |||
| Perroud et al., 2010 | ||||||||
| Hung et al., 2011 | ||||||||
| Moya et al., 2013 | ||||||||
| Stacey et al., 2013 | ||||||||
| 16 | chr17:30237152 | c.-1760T>C | NA | Obsessive-compulsive disorder, association with | Wendland et al., 2008 | |||
| Fuxman Bass et al., 2015 | ||||||||
| 17 | chr17:30222880 | c.-185A>C | NA | Major depressive disorder, association with | Rao et al., 2017 | |||
| 18 | chr17:30197993 | c.463T>G | NA | Increased expression | Vallender et al., 2008 | |||
| Seneviratne et al., 2009 | ||||||||
| 19 | chr17:30197786 | c.670T>G | Na | Panic disorder, association with | Gyawali et al., 2010 | |||
| Aoki et al., 2010 | ||||||||
| Hartley et al., 2012 | ||||||||
| Deletion | ||||||||
| 20 | Promoter | c.1212-1255 del TGCAGCC | NA | Anxiety related traits, association with | Helis et al., 1996 | |||
| Marziniak et al., 2005 | ||||||||
| Borroni et al., 2006 | ||||||||
| Albani et al., 2009 | ||||||||
| Location | Repetition Sequence | Number Of Repetitions | Reported Disease/Phenotype | Referance | ||||
| 21 | Intron 2 | (GGCTGYGACCYRGRRTG)n | 10-12 | Unipolar disorder, association with | Ogilvie et al., 1996 | |||
| 22 | Intron 2 | (GGCTGYGACCYRGRRTG)n | 12 | Pulmonary arterial hypertension, association with | Allen et al., 2008: | |||
| Cao et al., 2009 | ||||||||
Table 2. Solute Carrier Family 6 Member 4 (SLC6A4) related mutations.
Implicated in
Top note
The serotonin carrier protein encoded by SLC6A4 gene is the target of serotonin selective reuptake inhibitors, an important class of antidepressant drugs (Ramoz et al., 2006). Three alleles of 17-bp VNTR (variable number tandem repeat) were detected in the intron 2 region of the gene, between 9 (Stin2.9), 10 (Stin2.10), and 12 (Stin2.12) copies. Presence of Stin2.9 allele in humans has been reported to increase the risk of Major depressive disorder (MDD) (Ogilvie et al., 1996). The 5-HTTLPR promoter sequence of the gene comprises two variant repeat length polymorphisms, known as the 16-element long (L) and 44-bp short (S) variant with 14 repetitive elements (Esterling et al., 1998; Sen et al., 2004). The L/L genotype from the 5-HTTLPR promoter variants causes more 5-HTT protein expression than the L/S or S/S variants (Canli and Lesch, 2007). Analysis of lymphoblastoid cell lines with different genotypes revealed that the basal activity of the L variant of the SLC6A4 gene promoter was two times greater than that of the S variant (Lesch et al., 1996). In a later study, the expression of the native SLC6A4 gene in cultured lymphoblast cell lines from subjects with different SLC6A4 promoter genotypes was examined (Lesch et al., 1996).The mRNA concentration of the SLC6A4 gene in L/L cells was found to be 1.4 to 1.7-fold higher than the L/S and S/S cells (Lesch et al., 1996). Bradley et al. (2005) directly measured serotonin transporter mRNA levels and also identified 4 loci containing the serotonin transporter gene from 85 independent lymphoblast lines. They found strong impact of 5-HTTLPR on the mRNA exression (Bradley et al., 2005).
The Gly56Ala substitution in the exon 2 of the SLC6A4 gene has been reported to be associated with autism and exhibit structurally high SERT activity (Sutcliffe et al., 2005). I425V substitution in the exon 9 of the SLC6A4 gene has been reported to be associated with obsessive-compulsive disorder (OCD) (Ozaki et al., 2003; Kilic et al., 2003; Zhang et al., 2007). In addition, A-1438G and T102C polymorphisms were reported to be associated with OCD (Taylor, 2013; Taylor, 2016). Rao et al. (2017) reported that I550V (exon 12) and K605N (exon 13) substitutions of the SLC6A4 gene are associated with major depression disorder (MDD) and SA (non-fatal suicidal behavior) in addition to autism and OCD in 36 Chinese patients.
Animal Experiments
When 5-HTT was temporarily inhibited by fluoxetine (selective serotonin re-uptake inhibitor) in the early developmental period of mice, it was observed that adult mice exhibited abnormal emotional behaviors. It has been reported that serotonin plays a critical role in the maturation of brain systems that regulate emotional function, and that the low expression level of the SLC6A4 gene may be related to the development of psychiatric disorders in adults (Ansorge et al., 2004). A study of transgenic mice overexpressing the SLC6A4 gene and wild-type mice showed that right ventricular pressure was 3-fold higher in transgenic mice (Maclean et al., 2004). Page et al. (2009) reported macrocephaly in Pten +/- mice. Female Pten +/- mice had socialization disorder, whereas male Pten +/- mice had no socialization disorder. This phenotype was exacerbated in mice with Pten and SLC6A4 double haploinsufficiency. As a result of these findings PTEN and SLC6A4 genes have been reported to be associated with autism spectrum disorder (ASD).
The Gly56Ala substitution in the exon 2 of the SLC6A4 gene has been reported to be associated with autism and exhibit structurally high SERT activity (Sutcliffe et al., 2005). I425V substitution in the exon 9 of the SLC6A4 gene has been reported to be associated with obsessive-compulsive disorder (OCD) (Ozaki et al., 2003; Kilic et al., 2003; Zhang et al., 2007). In addition, A-1438G and T102C polymorphisms were reported to be associated with OCD (Taylor, 2013; Taylor, 2016). Rao et al. (2017) reported that I550V (exon 12) and K605N (exon 13) substitutions of the SLC6A4 gene are associated with major depression disorder (MDD) and SA (non-fatal suicidal behavior) in addition to autism and OCD in 36 Chinese patients.
Animal Experiments
When 5-HTT was temporarily inhibited by fluoxetine (selective serotonin re-uptake inhibitor) in the early developmental period of mice, it was observed that adult mice exhibited abnormal emotional behaviors. It has been reported that serotonin plays a critical role in the maturation of brain systems that regulate emotional function, and that the low expression level of the SLC6A4 gene may be related to the development of psychiatric disorders in adults (Ansorge et al., 2004). A study of transgenic mice overexpressing the SLC6A4 gene and wild-type mice showed that right ventricular pressure was 3-fold higher in transgenic mice (Maclean et al., 2004). Page et al. (2009) reported macrocephaly in Pten +/- mice. Female Pten +/- mice had socialization disorder, whereas male Pten +/- mice had no socialization disorder. This phenotype was exacerbated in mice with Pten and SLC6A4 double haploinsufficiency. As a result of these findings PTEN and SLC6A4 genes have been reported to be associated with autism spectrum disorder (ASD).
Entity name
Breast cancer
Note
High expression is found in breast cancer, but the gene product is not prognostic according to The Human Protein Atlas.
A fusion gene PIP4K2B /SLC6A4 was found in breast cancer (Yoshida et al., 2013).
A fusion gene PIP4K2B /SLC6A4 was found in breast cancer (Yoshida et al., 2013).
Entity name
Obsessive-Compulsive Disorder (OCD)
Note
Hu et al. (2006) found that the gain-of-function homozygous L(A)L(A) genotype was 2-fold in patients with OCD compared to healthy individuals. In a replication study in 175 trios consisting of probands with OCD and their parents, the L(A) allele was 2-fold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerted 1.8-fold effect on risk of OCD, thus establishing the role of the HTT gene in OCD. In another study, the frequency of Stin2.12 allele in Asian patients with anxiety disorder (including OCD) was reported to be significantly higher compared to the healthy individuals (Ohara et al., 1998). There is also a possible association between OCD and Stin2.12 allele in Spanish Caucasian population (Baca-Garcia et al., 2007; Saiz et al., 2008).
Entity name
Anxiety-Related Personality Traits
Note
The homozygous or heterozygous form of the S-variant of the 5-HTTLPR polymorphism in the SLC6A4 gene has been reported to be associated with lower expression and openness, and higher neuroticism (Lesch et al., 1996). Individuals with 1-2 copies of the S-variant of the 5-HTTLPR polymorphism, which is implicated in reduced 5-HTT expression and function and increased fear and anxiety-related behaviours, demonstrated higher amygdala activity in response to fearful stimuli compared with individuals homozygous for the L-variant (Hariri et al., 2002). The altered function of the serotonin neurotransmission system causes aggressive behaviour in Alzheimers patients (AD) (Brown et al., 1982; Palmer et al., 1988). In a study conducted on 137 AD patients, the aggressive behaviours (58 patients) were associated with L/L genotype (Sukonick et al., 2001).
Entity name
Major Depressive Disorder (MDD)
Note
People with L/S or S/S allele in stressful life conditions have been reported to have more depression and suicidal tendency than those with L/L allele (Caspi et al., 2003). They also reported that the individuals response to environmental insults was determined by environmental-gene interaction (Caspi et al., 2003). In a study conducted on Pomerania population, the relationship of S-variant with environmental interaction and depression was determined. The results of the study supported previous studies on the gene-environment interaction of the S allele. It has also been revealed to cause high mental vulnerability to social stress and chronic diseases (Grabe et al., 2005). Homozygous or heterozygous genotypes of the S-variant were associated with stress-related depression and anxiety disorders in elite athletes (Petito et al., 2016). The 5-HTTLPR polymorphisms of the SLC6A4 gene have been reported to be associated with prenatal and postnatal depression (Sanjuan et al., 2008; Oberlander et al., 2013). Interestingly, the genetic and epigenetic variations have been reported in the SLC6A4 gene of children exposed to prenatal depression (Devlin et al., 2010; Oppenheimer et al., 2013; Wankerl et al., 2014; Babineau et al., 2014; Green et al., 2017). 5-HTTLPR polymorphisms and DNA methylations of SLC6A4 gene have been reported to be associated with depression (Devlin et al., 2010; Sugawara et al., 2013).
Entity name
Seasonal Affective Disorder (SAD)
Note
Willeit et al. (2003) genotyped 284 subjects (138 SAD patients and 146 healthy individuals) to examine the relationship between L and S-variants in the 5-HTTLPR polymorphism of SLC6A4 gene with SAD. The distribution of genotype and S allele frequency was found similar between patients and healthy subjects, while they were correlated with the subtypes of DSM-IV depression. L allele was correlated with melancholic depression whereas S allele was related to atypical depression. It was concluded that 5-HTTLPR polymorphism affects the phenotypic disease expression but it is not the cause of disease.
The effects of light therapy on serotonin transporter binding (5-HTT BPND), which is biomarker of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter was studied. In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC with respect to placebo, whereas in the fall, no significant change in 5-HTT BPND was measured. In this context, it has been reported that 5-HTT BPND can be used as a biomarker for the assessment of the modification effects of light therapy (Harrison et al., 2015). In a study on 20 SAD patients and 20 healthy participants the impact of seasonal (winter and summer) variations on 5-HTT activity was investigated by analysing brain 5-HTT BPND levels. The study reported a significant increase in 5-HTT BPND in different brain regions (including ACC and PFC) especially in severe SAD during winter. The 5-HTT BPND as biomarker in the diagnosis of SAD is important as it can be applied for the development of prevention strategies against disease progress (Tyrer et al., 2016).
The effects of light therapy on serotonin transporter binding (5-HTT BPND), which is biomarker of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter was studied. In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC with respect to placebo, whereas in the fall, no significant change in 5-HTT BPND was measured. In this context, it has been reported that 5-HTT BPND can be used as a biomarker for the assessment of the modification effects of light therapy (Harrison et al., 2015). In a study on 20 SAD patients and 20 healthy participants the impact of seasonal (winter and summer) variations on 5-HTT activity was investigated by analysing brain 5-HTT BPND levels. The study reported a significant increase in 5-HTT BPND in different brain regions (including ACC and PFC) especially in severe SAD during winter. The 5-HTT BPND as biomarker in the diagnosis of SAD is important as it can be applied for the development of prevention strategies against disease progress (Tyrer et al., 2016).
Entity name
Alcoholism
Note
A meta-analysis study (data from 3,489 alcoholics and 2,325 controls) was conducted on the association of 5-HTTLPR polymorphisms of SLC6A4 with alcohol dependence. It has been reported that alcohol dependence complicated by a comorbid psychiatric condition or a more severe form of alcoholism is associated with the S-variant (Feinn et al., 2005). In a study conducted on university students, the S-variant was reported to be associated with high alcohol consumption (Herman et al., 2003). High alcohol consumption in men with homozygous or heterozygote genotypes of the S-variant has been reported, whereas it was seen only in the heterozygous women (Munaf et al., 2005). In a study conducted on 273 (78.5% male) alcoholic individuals of the Caucasus and Hispanic origin, it was reported that G allele carriers for the rs1042173 SNP in the 3UTR region of the SLC6A4 gene had lower alcohol consumption than T-allele homozygotes (Seneviratne et al., 2009). G allele transfection to HeLa cells resulted in higher mRNA and protein expression compared to T allele transfected cells (Seneviratne et al., 2009).
Entity name
Sudden Infant Death Syndrome (SIDS)
Note
L/L genotype and excess of L-variant have been reported to be associated with SIDS (Narita et al., 2001; Weese-Mayer et al., 2003). In addition, the Stin2.12 allele has been associated with SIDS in African-Americans and Japanese, whereas it is not associated with SIDS in Caucasian-Americans (Narita et al., 2001; Weese-Mayer et al., 2003).
Entity name
Panic Disorder (PD)
Note
The rs3813034 variant in the 3UTR region of the SLC6A4 gene has been reported to be related to PD (Gyawali et al., 2010). Decreased SLC6A4 gene expression due to the gene polymorphisms in midbrain, hypothalamus and temporal lobe has been associated with PD (Maron et al., 2006). Strug et al. (2010) reported that rs140701 variant of the SLC6A4 gene may be associated with PD.
Entity name
Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness (MDI)
Note
The disorder of the neurotransmitter system, including serotonin and monoamines, has been reported to be associated with bipolar disorder (Scott et al., 1979; Kapur and Remington, 1992). The patients with BPAD without panic disorder exhibited statistically higher frequencies of the Catechol O-Methyltransferase (COMT) Met158 and the S-variant 5-HTTLPR genotypes with respect to healthy individuals (Rotondo et al., 2002). When the relationship between L and S-variant polymorphisms of SLC6A4 gene and BPAD and unipolar depression were investigated by meta-analysis study, it was revealed that the S-variant could be associated with BPAD but not with unipolar depression. The L-variant was not implicated in BPAD and/or unipolar depression (Lasky-Su et al., 2005). However other studies reported no significant relationship between SLC6A4 5-HTTLPR and VNTR polymorphisms and BPAD (Mendlewicz et al., 2004; Cho et al., 2005). The association between epigenetic variations of SLC6A4 gene and BPAD were studied on 20 bipolar monozygotic twins with respect to 20 healthy subjects. The promoter-wide DNA methylation analysis of lymphoblastic cell lines (LCLs) revealed DNA hypermethylation in SLC6A4 gene that can be an epigenetic mark resulting from a G×E interaction leading to the development of BPED (Sugawara et al., 2011). In a study on the association of SLC6A4 and DRD2 (dopamine D2 receptor) genes with BPED, the gender specific differences in SLC6A4 gene polymorphisms were reported. The results revealed gender-specific association of the DRD2 A1/A1 and the 5-HTTLPR S/S, S/LG, and LG/LG (S+) genotypes in type I and type II men, but not in women. A significant interaction for the DRD2 A1/A1 and 5-HTTLPR S+ polymorphisms was also found only in type I and type II men (Wang et al., 2014).
Entity name
Pulmonary Hypertension (PPH)
Note
Smooth muscle cells (SMC) of pulmonary artery in PPH patients grow faster than controls when 5-HTT expression is stimulated by serotonin. As a result of these findings, 5-HTT has been shown to play a key role in the pathogenesis of SMC proliferation and 5-HTT polymorphisms are associated with PHH (Eddahibi et al., 2001). The higher 5-HTT expression was reported in pulmonary artery SMC in patients with L/L genotypes compared to L/S and S/S genotypes, resulting in more severe PPH. (Eddahibi et al., 2003). In a study on the association of idiopathic PPH with 5-HTT polymorphism in children, the L/L genotype has been reported to be associated with the aetiology of PPH (Vachharajani and Saunders, 2005).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 21183371 | 2011 | 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 |
| 19270731 | 2009 | The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network. | Ahmed BA et al |
| 18227069 | 2008 | Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter. | Ahmed BA et al |
| 19521089 | 2009 | Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy. | Albani D et al |
| 18583979 | 2008 | Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. | Allen NC et al |
| 15514160 | 2004 | Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. | Ansorge MS et al |
| 20303273 | 2010 | The association between personality, pain threshold and a single nucleotide polymorphism (rs3813034) in the 3'-untranslated region of the serotonin transporter gene (SLC6A4). | Aoki J et al |
| 24827922 | 2015 | Prenatal depression and 5-HTTLPR interact to predict dysregulation from 3 to 36 months--a differential susceptibility model. | Babineau V et al |
| 17174018 | 2007 | Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene. | Baca-Garcia E et al |
| 16582043 | 2006 | Cumulative effect of COMT and 5-HTTLPR polymorphisms and their interaction with disease severity and comorbidities on the risk of psychosis in Alzheimer disease. | Borroni B et al |
| 15858822 | 2005 | Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. | Bradley SL et al |
| 17506858 | 2007 | Plasma serotonin levels and the platelet serotonin transporter. | Brenner B et al |
| 6177256 | 1982 | Aggression, suicide, and serotonin: relationships to CSF amine metabolites. | Brown GL et al |
| 22622072 | 2012 | SLC6A4 rare variant associated with eating disorders in Mexican patients. | Camarena B et al |
| 17726476 | 2007 | Long story short: the serotonin transporter in emotion regulation and social cognition. | Canli T et al |
| 19886858 | 2009 | Association study of serotonin transporter gene polymorphisms and ventricular septal defects related possible pulmonary arterial hypertension in Chinese population. | Cao H et al |
| 12869766 | 2003 | Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. | Caspi A et al |
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Other Information
Locus ID:
NCBI: 6532
MIM: 182138
HGNC: 11050
Ensembl: ENSG00000108576
Variants:
dbSNP: 6532
ClinVar: 6532
TCGA: ENSG00000108576
COSMIC: SLC6A4
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA10074 | escitalopram | Chemical | ClinicalAnnotation, VariantAnnotation | ambiguous | PD | 19272758, 19567893, 20212518, 23095326, 24014145 | |
| PA124 | CYP2C19 | Gene | DataAnnotation | associated | |||
| PA128 | CYP2D6 | Gene | DataAnnotation | associated | |||
| PA128406954 | Weight gain | Disease | VariantAnnotation | associated | PD | ||
| PA164713257 | Selective serotonin reuptake inhibitors | Chemical | ClinicalAnnotation, Literature, MultilinkAnnotation, VariantAnnotation | associated | PD | 17414739, 19204908, 22086748, 24930681, 28639488 | |
| PA164784024 | peginterferon alfa-2b | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | ||
| PA165860788 | evodiamine | Chemical | VariantAnnotation | associated | PK | 21647174 | |
| PA165860812 | berberine | Chemical | VariantAnnotation | associated | PK | 21647174 | |
| PA166048714 | Pregnancy | Disease | VariantAnnotation | associated | PD | 28639488 | |
| PA193 | HTR2A | Gene | DataAnnotation | associated | |||
| PA27093 | CYP1A2 | Gene | DataAnnotation | associated | |||
| PA443309 | Alcoholism | Disease | ClinicalAnnotation, VariantAnnotation | associated | PD | 21247998, 31595439 | |
| PA443853 | Dementia | Disease | VariantAnnotation | associated | PD | ||
| PA443928 | Dizziness | Disease | VariantAnnotation | associated | PD | 23859574 | |
| PA443937 | Drug Toxicity | Disease | ClinicalAnnotation | associated | PD | 20031235, 23859574 | |
| PA444367 | Heart Defects, Congenital | Disease | VariantAnnotation | associated | PD | 28639488 | |
| PA444624 | Sleep Initiation and Maintenance Disorders | Disease | VariantAnnotation | associated | PD | 14573314 | |
| PA445043 | Opioid-Related Disorders | Disease | ClinicalAnnotation, VariantAnnotation | associated | PD | 29333880 | |
| PA445048 | Nausea | Disease | VariantAnnotation | not associated | PD | 12208565, 17697394 | |
| PA445208 | Pain | Disease | ClinicalAnnotation | associated | PD | 32432768 | |
| PA445452 | Psychomotor Agitation | Disease | VariantAnnotation | associated | PD | 14573314 | |
| PA445876 | Tobacco Use Disorder | Disease | ClinicalAnnotation | associated | PD | 21658141 | |
| PA446863 | Hepatitis C, Chronic | Disease | ClinicalAnnotation, VariantAnnotation | associated | PD | ||
| PA447197 | Attention Deficit Disorder with Hyperactivity | Disease | VariantAnnotation | not associated | PD | 17948872 | |
| PA447207 | Depressive Disorder | Disease | ClinicalAnnotation, VariantAnnotation | ambiguous | PD | 11543734, 16515395, 17697394, 19272758, 19451862, 19567893, 20212518, 23510446, 24014145 | |
| PA447209 | Mood Disorders | Disease | ClinicalAnnotation, VariantAnnotation | ambiguous | PD | 10653220, 10683861, 11027924, 15274037, 15520364, 15812265, 16874005, 17146470, 17853254, 17914325, 18983505, 18987562, 19606452, 19800133, 23288236 | |
| PA447211 | Obsessive-Compulsive Disorder | Disease | VariantAnnotation | not associated | PD | 12082589 | |
| PA447212 | Panic Disorder | Disease | VariantAnnotation | ambiguous | PD | 16034444, 16822601, 19259652, 19800133, 21688171 | |
| PA447216 | Schizophrenia | Disease | VariantAnnotation | associated | PD | 20031235, 20452607 | |
| PA447278 | Depression | Disease | ClinicalAnnotation, DataAnnotation, VariantAnnotation | ambiguous | PD | 10683861, 12374640, 16302021, 17018806, 18253134, 19272758, 19567893, 20212518, 24014145 | |
| PA447321 | Depressive Disorder, Major | Disease | ClinicalAnnotation, DataAnnotation, VariantAnnotation | ambiguous | PK | PD | 10653220, 10683861, 11027924, 11543734, 11817517, 12082589, 12208565, 12476327, 12955294, 14573314, 14624186, 15274037, 15520364, 15812265, 15993855, 16302021, 16580768, 16874005, 17018806, 17414739, 17606812, 17853254, 17914325, 18253134, 18452396, 18987562, 19272758, 19468717, 19567893, 19606452, 19800133, 19825907, 20584552, 20640435, 21962566, 22885912, 23095326, 23288236, 23510446, 24014145, 27439447, 9857976 |
| PA448073 | ethanol | Chemical | ClinicalAnnotation | associated | PD | 31595439 | |
| PA448685 | buprenorphine | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 29333880 | |
| PA448687 | bupropion | Chemical | ClinicalAnnotation | associated | PD | 21658141 | |
| PA449015 | citalopram | Chemical | ClinicalAnnotation, Pathway, VariantAnnotation | ambiguous | PD | 14624186, 17606812, 18618621, 19468717, 19741567, 19996755, 20640435, 23510446, 23973251 | |
| PA449048 | clomipramine | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 10867985 | |
| PA449061 | clozapine | Chemical | VariantAnnotation | associated | PD | 20452607 | |
| PA449673 | fluoxetine | Chemical | ClinicalAnnotation, Pathway, VariantAnnotation | ambiguous | PD | 10683861, 12476327, 14573314, 15993855, 16302021, 17018806, 19468717, 19741567, 20584552, 20640435, 22885912, 27439447 | |
| PA449690 | fluvoxamine | Chemical | ClinicalAnnotation, Pathway, VariantAnnotation | ambiguous | PD | 11543734, 11817517, 12082589, 12208565, 12374640, 15274037, 15812265, 16874005, 19741567, 23288236, 9857976 | |
| PA449841 | haloperidol | Chemical | MultilinkAnnotation, VariantAnnotation | associated | PD | 20031235, 27023437 | |
| PA450401 | methadone | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 29333880 | |
| PA450464 | methylphenidate | Chemical | VariantAnnotation | not associated | PD | 17948872 | |
| PA450522 | mirtazapine | Chemical | ClinicalAnnotation, VariantAnnotation | ambiguous | PD | 15520364 | |
| PA450550 | morphine | Chemical | ClinicalAnnotation | associated | PD | 32432768 | |
| PA450657 | nortriptyline | Chemical | VariantAnnotation | not associated | PD | 11027924, 19567893 | |
| PA450688 | olanzapine | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 20031235, 23859574 | |
| PA450705 | ondansetron | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 21247998 | |
| PA450801 | paroxetine | Chemical | ClinicalAnnotation, Pathway, VariantAnnotation | ambiguous | PD | 10653220, 10683861, 11027924, 15274037, 15520364, 15812265, 16034444, 16822601, 16874005, 17697394, 17853254, 17914325, 18983505, 18987562, 19259652, 19468717, 19606452, 19741567, 19800133, 20640435, 21688171, 23288236 | |
| PA450966 | pindolol | Chemical | VariantAnnotation | not associated | PD | 9857976 | |
| PA451201 | quetiapine | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 20031235, 23859574 | |
| PA451241 | ribavirin | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | ||
| PA451257 | risperidone | Chemical | ClinicalAnnotation, VariantAnnotation | associated | PD | 20031235, 23859574 | |
| PA451333 | sertraline | Chemical | ClinicalAnnotation, Pathway, VariantAnnotation | ambiguous | PK | PD | 12955294, 16580768, 17018806, 18452396, 19741567, 19800133, 19825907, 21962566, 22885912 |
| PA451866 | venlafaxine | Chemical | VariantAnnotation | not associated | PD | 19468717, 24014145 | |
| PA452229 | antidepressants | Chemical | ClinicalAnnotation, VariantAnnotation | ambiguous | PD | 16515395, 17146470, 18253134, 19451862 | |
| PA452233 | antipsychotics | Chemical | VariantAnnotation | associated | PD | 20031235 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37070394 | 2024 | Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism. | 1 |
| 38103452 | 2024 | DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment. | 0 |
| 38288388 | 2024 | Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation. | 0 |
| 38361316 | 2024 | SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health. | 1 |
| 38465822 | 2024 | [The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression]. | 0 |
| 38753762 | 2024 | PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs. | 0 |
| 38928372 | 2024 | Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses. | 0 |
| 37070394 | 2024 | Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism. | 1 |
| 38103452 | 2024 | DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment. | 0 |
| 38288388 | 2024 | Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation. | 0 |
| 38361316 | 2024 | SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health. | 1 |
| 38465822 | 2024 | [The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression]. | 0 |
| 38753762 | 2024 | PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs. | 0 |
| 38928372 | 2024 | Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses. | 0 |
| 36649260 | 2023 | Unravelling neurotransmitters impairment in primary progressive aphasias. | 3 |
Citation
Rafig Gurbanov ; Berkay Kalkanci
SLC6A4 (solute carrier family 6 member 4)
Atlas Genet Cytogenet Oncol Haematol. 2019-03-01
Online version: http://atlasgeneticsoncology.org/gene/49951/slc6a4-(solute-carrier-family-6-member-4)
