Variant type:
Cytogenetic location:
Other names:
  • 44-BP INS/DEL
OMIM: 182138.0001

Clinical significance


Clinical significance:
Pathogenic/Likely pathogenic
Review status:
1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
  • Serotonin transporter activity, increased/decreased
See supporting ClinVar records

1 Affected Gene

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Assertion and evidence details


Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
(Last submitted)
Submission accession
(Mar 15, 2013)
classified by single submitter
(literature only)
literature only
  • Serotonin transporter activity, increased/decreased
unknownPubMed (32)
(Dec 30, 2010)


FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedunknownnot providednot provided


Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedunknown


Altered function of the serotonin neurotransmission system has been implicated in the aggressive behavior in patients with Alzheimer disease (AD; see 104300). Sukonick et al. (2001) studied 137 subjects diagnosed as having possible or probable AD, 58 of whom demonstrated aggressive behavior. They found that the *L/*L genotype was significantly associated with aggression in patients with AD (odds ratio, 2.8). Similar results were obtained for *L allele frequency.
Among 1,932 individuals, comprising 539 with unipolar affective disorder, 572 with bipolar disorder, and 821 controls, Mendlewicz et al. (2004) found no significant differences in genotype or allele frequency of the 5-HTTLPR polymorphism.
Cho et al. (2005) performed 2 metaanalyses of published studies involving serotonin transporter as a candidate gene for bipolar disorder. The studies were population-based and family-based studies investigating the association with the 5-HTTLPR promoter polymorphism and the intron 2 VNTR. Seventeen population-based studies comprising 1,712 cases and 2,583 controls and 6 family-based studies comprising 587 trios were included in the 5-HTTLPR metaanalysis. Sixteen population-based studies comprising 1,764 cases and 2,703 controls as well as for family-based studies comprising 382 trios were included in the intron 2 VNTR metaanalysis. Meta-regression showed that neither study type nor ethnic sample significantly contributed to heterogeneity of the metaanalyses. Overall, odds ratios suggested a very small but detectable effect of the serotonin transporter in susceptibility to bipolar disorder.
Comorbid panic disorder may define a subtype of bipolar disorder (125480) and may influence the strength of association found between bipolar disorder and candidate genes involved in monoamine neurotransmission. Rotondo et al. (2002) studied the frequency of the 5-HTTLPR polymorphism, the V158M polymorphism of catechol-O-methyltransferase (COMT; 116790.0001), and a splice site polymorphism (IVS7+218C-A) of tryptophan hydroxylase (TPH; 191060) in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. They compared results from DNA extracted from blood leukocytes of 111 unrelated subjects of Italian descent meeting DSM-III-R criteria for bipolar disorder, including 49 with and 62 without comorbid lifetime panic disorder, with those of 127 healthy subjects. Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT met158 and the short 5-HTTLPR alleles. No statistical significance was found between the bipolar disorder groups and the TPH polymorphism. Rotondo et al. (2002) concluded that bipolar disorder without panic disorder may represent a more homogeneous form of illness and that variants of the COMT and SLC6A4 genes may influence clinical features of bipolar disorder.
Eddahibi et al. (2001) reported that pulmonary artery smooth muscle cells (SMCs) from patients with primary pulmonary hypertension (PPH; see 178600) grew faster than those from controls when stimulated with serum or serotonin, due to increased expression of 5-HTT. Inhibitors of 5-HTT attenuated the growth-stimulatory effects of serum and serotonin. Expression of 5-HTT was increased in cultured pulmonary artery SMCs as well as in platelets and lungs from patients with PPH, where it predominated in the media of thickened pulmonary arteries and in onion bulb lesions. The L allele of the 5-HTT promoter, which is associated with 5-HTT overexpression and increased pulmonary artery SMC growth, was present in homozygous form in 65% of PPH patients but in only 27% of controls (p less than 0.001). Eddahibi et al. (2001) concluded that 5-HTT activity plays a key role in the pathogenesis of pulmonary artery SMC proliferation in PPH and that a 5-HTT polymorphism confers susceptibility to PPH.
Feinn et al. (2005) conducted a metaanalysis of the association of the functional serotonin transporter promoter polymorphism with alcohol dependence (103780). The metaanalysis was from data collected from 17 published studies including 3,489 alcoholics and 2,325 controls. The frequency of the short allele was significantly associated with alcohol dependence (OR, 1.18, 95% CI, 1.03-1.33). A greater association with the S allele was seen among individuals with alcohol dependence complicated by either a comorbid psychiatric condition or an early-onset or more severe alcoholism subtype (OR, 1.34, 95% CI, 1.11-1.63).
Following up on a study by Herman et al. (2003) that showed an association between the SLC6A4 short form of the promoter polymorphism and alcohol consumption in a college population, Munafo et al. (2005) studied 755 individuals, aged 33 to 73 years, who were recruited from general practices in the U.K. as part of a study of genetic associations with smoking cessation. Subjects were assessed for age, gender, body mass index, weekly alcohol consumption, ethnicity, and smoking habits. Individuals who were nondrinkers were excluded from the study. Genotyping was done for SLC6A4 long and short promoter polymorphisms. The short allele was significantly associated with increased alcohol consumption (p = 0.03). There was suggestive evidence of a genotype-sex interaction (p = 0.04). Post hoc analysis indicated higher alcohol consumption in men with one or more copies of the short allele, whereas consumption in women was highest among heterozygotes compared to both homozygote groups.
Grabe et al. (2005) studied 1,005 subjects from a general Pomeranian population sample to determine the potential environmental interaction with the short allele of the promoter region of the SLC6A4 gene and depression. Significant interactions between genotype, unemployment, and chronic diseases were found in females but not in males. The genotype explained 2% of the total variance of the rating scale used and 9.1% of the explained variance. The results supported previous findings of a significant gene-environmental interaction of the short allele indicating a higher mental vulnerability to social stressors and chronic disease.
Hariri et al. (2002) reported that individuals with 1 or 2 copies of the short allele of the serotonin transporter promoter polymorphism, which has been associated with reduced serotonin expression and function and increased fear and anxiety-related behaviors, exhibited greater amygdala neuronal activity, as assessed by functional MRI, in response to fearful stimuli compared with individuals homozygous for the long allele. Each group consisted of 14 adults. Hariri et al. (2002) concluded that their results demonstrated genetically driven variation in the response of brain regions underlying human emotional behavior and suggested that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
Heils et al. (1995, 1996) reported that a polymorphism in the promoter region of the serotonin transporter gene (referred to as 5-HTTLPR) is located approximately 1 kb upstream of the SLC6A4 transcription initiation site and is composed of 16 repeat elements. The polymorphism consists of a 44-bp insertion or deletion involving repeat elements 6 to 8. The frequency of the long allele was found by Lesch et al. (1996) to be 57% and of the short allele 43%.
Hu et al. (2006) found that the gain-of-function homozygous L(A)L(A) genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (164230) than in 253 ethnically matched controls. 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 a moderate (1.8-fold) effect on risk of OCD, thus establishing a role for the HTT gene in OCD.
Hu et al. (2006) showed that 5-HTTLPR is functionally triallelic. The L(G) allele, which is the L allele with a common A-to-G substitution (rs2553), creates a functional AP2 transcription factor (107580) binding site. Expression assays in 62 lymphoblastoid cell lines representing the 6 genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and L(G) alleles, accounting for more variation in HTT expression than previously recognized.
In 103 patients with chronic obstructive pulmonary disease (COPD; see 606963), Eddahibi et al. (2003) determined the 5-HTTLPR genotype and measured pulmonary artery pressure. They found that patients carrying the LL genotype, which is associated with higher levels of 5-HTT expression in pulmonary artery smooth muscle cells than the LS and SS genotypes, had more severe pulmonary hypertension than LS or SS patients (p less than 0.01). Eddahibi et al. (2003) concluded that the 5-HTTLPR genotype appears to determine the severity of pulmonary hypertension in patients with COPD.
In 114 healthy Caucasian controls, Pezawas et al. (2005) found that carriers of the short allele had significantly reduced gray matter volume of the perigenual anterior cingulate cortex (pACC) and amygdala compared to those with the long allele. Functional MRI of 94 control individuals during perceptual processing of fear stimuli showed functional connectivity between these 2 regions, suggesting a feedback circuit. Carriers of the short allele had highly significant reduction of amygdala-pACC connectivity, particularly with the rostral ACC, compared to carriers of the long allele. Pezawas et al. (2005) postulated that carriers of the short allele have functional uncoupling of this mood circuit, reflecting differential brain development of these core regions. The differences may underlie normal emotional reactivity and influence genetic susceptibility for depression.
In a functional MRI study of 29 healthy males, Heinz et al. (2005) found that the number of S alleles was positively correlated with activation of the amygdala in response to the viewing of aversive, but not pleasant, pictures. Carriers of the S allele also showed increased coupling between the amygdala and the ventromedial prefrontal cortex, suggesting that S carriers have increased capacity for emotional states and possibly for the development of depression in response to adverse events.
In a prospective-longitudinal study of a representative birth cohort, Caspi et al. (2003) tested why stressful experiences led to depression (608516) in some people but not in others. The functional polymorphism in the promoter region of the serotonin transporter gene was found to moderate the influence of stressful life events on depression. Individuals with 1 or 2 copies of the short allele of the promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. The Dunedin Multidisciplinary Health and Development Study Cohort was used for this study. It consists of a birth cohort of 1,037 children, of whom 52% were male, that was assessed at ages 3, 5, 7, 9, 11, 13, 15, 18, and 21 and was virtually intact at the age of 26 years. A total of 847 Caucasian non-Maori study members were divided into 3 groups on the basis of their genotype. There was no difference in genotype frequencies between the sexes. Stressful life events occurring after the 21st birthday and before the 26th birthday were assessed with the aid of a life-history calendar, a highly reliable method for ascertaining life event histories. Thirty percent of the study members experienced no stressful life events, 25% experienced 1 event, 20% 2 events, 11% 3 events, and 15% 4 or more events. There were no significant differences between the 3 genotype groups in the number of life events they experienced, suggesting that the serotonin transporter genotype did not influence exposure to stressful life events. In a hierarchical logistic regression model, the main effect of genotype was not significant, the main effect of number of life events was significant, and the interaction between genotype and number of life events was significant. Caspi et al. (2003) concluded that their epidemiologic study provided evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
In a study of 466 patients with major depressive disorder and 836 control subjects of German descent, Hoefgen et al. (2005) found that the short allele was significantly more frequent in patients than in control subjects (45.5% vs 39.9%; p = 0.006; odds ratio = 1.26).
Lasky-Su et al. (2005) conducted a metaanalysis on case-control studies of the association between 2 polymorphisms of the serotonin transporter gene (a 17-bp VNTR in intron 2, and a 44-bp insertion/deletion in the promoter region) and affective disorders (bipolar disorder and unipolar depression) resulting in 4 metaanalyses. For each polymorphism, the authors assessed the evidence for allelic association, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short alleles of the 44-bp insertion/deletion polymorphism showed a significant association with bipolar disorder (OR = 1.13, p = 0.001) but not unipolar disorder. The VNTR had no association with either disorder.
Lesch et al. (1996) found that the short version of the 5-HTTLPR polymorphism in either homozygous or heterozygous form was associated with higher neuroticism scores and lower extraversion and openness scores (see 607834).
Marziniak et al. (2005) found an increased frequency of the S allele in 96 patients with migraine with aura (see 157300) (56.3%) compared to 101 patients with migraine without aura (37.1%) and 115 controls (42.6%). The authors suggested that the decreased overall level of serotonergic transmission conferred by the S allele may be a factor in the pathogenesis of migraine with aura. Todt et al. (2006) found no association between the promoter length polymorphism in the SLC6A gene and migraine with aura among 472 German patients and 506 controls.
Murphy et al. (2004) studied the long/short polymorphism in the SLC6A4 gene because previous reports had identified an association between the S allele and decreased efficacy of selective serotonin reuptake inhibitors. They randomized 246 cognitively intact patients aged 65 years or older with major depression to either mirtazapine (a mixed noradrenergic and serotonergic antidepressant) or paroxetine hydrochloride (a serotonin reuptake inhibitor-type antidepressant) treatment for depression. Patients with the S allele treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the promoter polymorphism affected antidepressant efficacy; however, the promoter polymorphism had a dramatic effect on adverse events. Among paroxetine-treated patients, S allele carriers experienced significantly more severe adverse events, achieved significantly lower final daily doses, and had more discontinuations. Mirtazapine-treated patients had the opposite finding: S allele carriers had significantly fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. Murphy et al. (2004) concluded that the S allele of the SLC6A4 promoter polymorphism is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors.
Narita et al. (2001) and Weese-Mayer et al. (2003) found an excess of the L/L genotype and the L allele in association with sudden infant death syndrome (272120). Weese-Mayer et al. (2003) subsequently showed that an intron 2 polymorphism (12-repeat allele), which also differentially regulates 5-HTT expression, was associated with increased risk of SIDS in African American but not Caucasian SIDS cases.
Risch et al. (2009) performed a metaanalysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. They found no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.
Sen et al. (2004) noted that at least 26 studies had investigated a putative association between the functional serotonin transporter 5-HTTLPR promoter polymorphism and anxiety-related personality traits, with inconsistent results. They conducted a metaanalysis of these studies, which included 5,629 individuals, and found suggestive evidence for an association between the short allele (S) and increased anxiety-related personality trait scores (p = 0.087). Analysis of heterogeneity revealed that substantial variation was introduced by the inventories used; when analyses were stratified by inventory type, there was a significant association between 5-HTTLPR and neuroticism as measured by the NEO personality inventory (p = 0.000016) but not by other rating scales. Sen et al. (2004) concluded that there is a strong association between the serotonin transporter promoter variant and neuroticism, and that nonreplications are largely due to small sample size and use of different inventories.
Smits et al. (2004) conducted a systematic review of the literature on the influence of the serotonin 5-HTTLPR L/S polymorphisms and intron 2 VNTR polymorphisms (STin2) on SSRI antidepressant response. The weighted mean decrease in depression score for patients with the S/S, S/L, and L/L genotypes were 35.4%, 46.3%, and 48.0% at week 4, respectively, and 53.9%, 54.6%, and 48.3% at week 6. Among Caucasian patients, both the mean decrease in depression scores and response rate were lowest in the S/S group. The 5-HTTLPR results were inconsistent in Asian patients. Among Asian patients, weighted response rates were 36.1% for the 10/12 STin2 genotype and 80.7% for the 12/12 genotype (chi square = 27.8, P less than 0.001).
Taylor et al. (2005) studied the influence of serotonin transporter promoter polymorphisms on hippocampal volumes in late-life depression. They genotyped and performed brain MRIs on 72 individuals with early-onset depression, 63 with late-onset depression, and 83 healthy controls. Subjects with late-onset depression who were homozygous for the long allele (L/L) had significantly smaller right hippocampal volumes than did L/L individuals with early-onset depression (p = 0.046) or L/L control individuals (p = 0.01). Post hoc analysis also showed that later age of depression onset was associated with smaller hippocampal volumes in individuals with the L/L genotype, but earlier age of onset was associated with smaller hippocampal volumes in individuals who were homozygous for the short allele.
Willeit et al. (2003) genotyped 138 patients with seasonal affective disorder (SAD; see 608516), which is usually a variant of major depressive disorder, and 146 healthy volunteers for the long/short promoter polymorphism. No difference between patients and controls was found for genotype distribution and allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depressive subtypes such that melancholic depression was associated with the long allele and atypical depression with the short allele (2-sided Fisher's exact test: genotype distribution, p = 0.0038; allele frequencies: p = 0.007). Willeit et al. (2003) concluded that their findings support the notion that the promoter region of the serotonin transporter influences phenotypic expression of disease but does not cause the disease.
Yu et al. (2002) tested the hypothesis that the 5-HTTLPR polymorphism is associated with SSRI antidepressant response by evaluating total and cluster depressive symptoms in 121 Chinese patients diagnosed with major depression. The results revealed that patients with the L/L genotype had a significantly better response to SSRI (fluoxetine) when compared to the S allele carriers on the basis of total (p = 0.013), core (p = 0.011), psychic anxiety (p = 0.005), and somatic anxiety (p = 0.002) symptoms of the Hamilton Depression Rating Scale-score percentage change.

Last Updated: Oct 30, 2014

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