17q11.2

5-HTT,5-HTTLPR,5HTT,HTT,OCD1,SERT,SERT1,hSERT

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).

Breast cancer

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).

Obsessive-Compulsive Disorder (OCD)

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).

Anxiety-Related Personality Traits

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).

Major Depressive Disorder (MDD)

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).

Seasonal Affective Disorder (SAD)

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).

Alcoholism

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).

Sudden Infant Death Syndrome (SIDS)

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).

Panic Disorder (PD)

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.

Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness (MDI)

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).

Pulmonary Hypertension (PPH)

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).