David Duffy (last updated 2005-Nov-03).
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]. | |
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 | |
S/L | 1133 | 50.6 | |
S/S | 751 | 50.3
|
The "Short" allele weakly increases anxiety (0.2 SD) and risk of major depression.
Bipolar Disorder | Violent Suicide | ||
---|---|---|---|
The "Short" allele weakly increases risk of bipolar disorder and violent suicide.
Author | Year | Country | Bipolar | Unipolar | Controls | Diagnosis | |||
---|---|---|---|---|---|---|---|---|---|
S | L | S | L | S | L | ||||
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 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].
Genotyped 847 Caucasians followed to age 26 (265:435:147):
Measured stressful life events from ages 21-26 (life-history calendar):
Assessed childhood maltreatment
Assessed depression in last 12 months (Diagnostic Interview Schedule)
Predicted values from fitted interaction models
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). |
Grabe et al [2004]: Distress (BL-38 scale) versus chronic disease and promoter genotype in Pomeranian women (N=674). |
Manuck et al [2004]: Prolactin level following fenfluramine administration versus SES and SLC6A4 promoter genotype (N=139). |
Eley et al [2004]: Depression risk in adolescent females versus hardship and adverse life events and SLC6A4 promoter genotype (N=230). |
Kendler et al [2005]: Depression risk in twins versus stressful life events and SLC6A4 promoter genotype (N=549). |
Sjoberg et al [2005]: Depressive symptoms in girls versus familial conflict and SLC6A4 promoter genotype (N=114). |
Surtees et al [2005]: Major depression (previous 12 months) versus number of stressful life events in previous 5 years (N=4175). |
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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