The serotonin transporter gene (SLC6A4) promoter polymorphism

David Duffy (last updated 2005-Nov-03).

The serotonin transporter gene (SLC6A4) promoter polymorphism

There is a common VNTR polymorphism in the promoter of the serotonin transporter gene (often called 5-HTTLPR). SLC6A4-promoter/luciferase reporter construct is expressed at higher levels if the 42 bp insertion ("long") is present (16 repeat versus 14 repeat) [Heils et al 1994; Lesch et al 1996].
SERT promoter SERT promoter indel

SLC6A4 promoter polymorphism and behaviour

Given the effects of drugs on the serotonin transporter, it seemed likely that there may be phenotypic effects of this polymorphism on behaviour:

Trait Anxiety Major (unipolar) Depression
Genotype N Neuroticism
Score (NEO)
L/L 648 48.5 SERT indel and unipolar
S/L 113350.6
S/S 751 50.3

The "Short" allele weakly increases anxiety (0.2 SD) and risk of major depression.

SLC6A4 promoter polymorphism and behaviour 2

Bipolar DisorderViolent Suicide
SERT indel and bipolar SERT indel and suicide

The "Short" allele weakly increases risk of bipolar disorder and violent suicide.

Meta-analysis data

Author Year Country Bipolar Unipolar Controls Diagnosis
Bellivier 1998 France 190 218 40 50 82 116 DSM-IV
Collier 1996 Germany 39 39 41 53 243 359 DSM-IV
Collier 1996 England 191 189 82 80 155 193 DSM-IV
Collier 1996 Italy 66 84 22 22 82 108 DSM-IV
Furlong 1998 United Kingdom 76 98 116 134 139 199 DSM-IV.SADS-L
Frisch 1999 Israel Ashk NA NA 56 70 116 108 DSM-IV.SADS-L
Frisch 1999 Israel non-Ashk NA NA 58 62 38 40 DSM-IV.SADS-L
Gutierrez 1998 Spain 85 91 NA NA 105 119 DSM-III-R
Hauser 2003 Poland 135 129 102 86 168 258 DSM-IV.ICD-10
Hoehe 1998 France,Germany 70 88 32 40 234 328 DSM-IV.SADS-L
Kim 2000 Asia NA NA 183 57 377 127 NA
Kunugi 1997 Japan 228 52 81 17 328 86 DSM-IV
Mellerup 2001 NA NA NA 72 112 89 127 NA
Mendlewicz 2004 Europe 520 624 436 642 712 930 RCD.DSM-III.R.DSM-IV
Minov 2001 NA NA NA 159 185 98 144 NA
Ohara 1998 Japan 51 17 65 17 140 44 NA
Oliveira 2000 Brazil 49 79 NA NA 151 243 NA
Oruc 1997 NA 40 32 NA NA 29 35 NA
Ospina-Duque 2000 Columbia 101 105 NA NA 119 105 DSM-IV
Rees 1997 United Kingdom 139 197 57 103 107 129 DSM-IV
Serretti 2002 Italy 690 888 579 755 367 547 DSM-IV.OPCRIT
Shcherbatykh 2000 Russia 37 43 63 103 224 324 NA

Caspi et al [2003]

Caspi and coworkers reported a study of the SLC6A4 promoter insertion-deletion in the Dunedin Multidisciplinary Health and Development Study cohort.

They argued that the weakness of the association might hide larger effects in different environments, and cite animal models.

For instance, in rhesus monkeys, the short allele predicts low CSF serotonin metabolite levels (5-HIAA), but in deprived (peer-reared) and not in maternally reared monkeys [Bennett et al 2002]. A similar interaction is seen for ACTH response to stress [Barr et al 2004].

Genotyping in Caspi et al [2003]

Genotyped 847 Caucasians followed to age 26 (265:435:147):

Life Events in Caspi et al [2003]

Measured stressful life events from ages 21-26 (life-history calendar):

Childhood maltreatment in Caspi et al [2003]

Assessed childhood maltreatment

Depression in Caspi et al [2003]

Assessed depression in last 12 months (Diagnostic Interview Schedule)

Results from Caspi et al [2003]

Predicted values from fitted interaction models

SERT indel GxE

Results from Caspi et al [2003] 2

Marginal effects of promoter genotype
on risk of recent major depression

Genotype Odds Ratio
L/L (31%) 1
S/L (51%) 1.16 (0.88-1.53)
S/S (18%) 1.35 (0.78-2.33)

Moderation by promoter genotype of
association of depression with life events.

Genotype Odds Ratio (per life event)
L/L (31%) 1.13 (0.83-1.56)
S/L (51%) 1.47 (1.08-2.02)
S/S (18%) 1.68 (1.22-2.30)


Kaufman et al [2004]: Depression score in children taken into care (N=57) versus controls (N=44).
Kauffman et al
Grabe et al [2004]: Distress (BL-38 scale) versus chronic disease and promoter genotype in Pomeranian women (N=674).
Grabe et al
Manuck et al [2004]: Prolactin level following fenfluramine administration versus SES and SLC6A4 promoter genotype (N=139).
Manuck et al
Eley et al [2004]: Depression risk in adolescent females versus hardship and adverse life events and SLC6A4 promoter genotype (N=230).
Eley et al
Kendler et al [2005]: Depression risk in twins versus stressful life events and SLC6A4 promoter genotype (N=549).
Kendler et al
Sjoberg et al [2005]: Depressive symptoms in girls versus familial conflict and SLC6A4 promoter genotype (N=114).
Sjoberg et al


Surtees et al [2005]: Major depression (previous 12 months) versus number of stressful life events in previous 5 years (N=4175).
Surtees et al

Population genetics of SLC6A4 promoter polymorphism

The frequency of the "short" allele varies across populations.

Group N Proportion s
Asian 551 0.77
Askenazi Israelis 224 0.52
UK 461 0.43
European Americans 221 0.43
Italy 552 0.41
African Americans 1210 0.23


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