Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT)

Rees, Mark I.; Norton, Nadine; Jones, Ian; McCandless, F.; Scourfield, Jane; Holmans, Peter Alan; Moorhead, Steve; Feldman, Eric A.; Sadler, Stephanie; Cole, Toby B.; Redman, Kate; Farmer, Anne; McGuffin, Peter; Owen, Michael John; Craddock, Nicholas John

doi:10.1038/sj.mp.4000256

Cited by 148 publications

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“…SERPR long and short allele frequencies were, respectively, 0.51 and 0.49, similar to those of previously published samples in Caucasians 45,59,69,70 and similar to those observed in our Italian sample (0.57 and 0.43, respectively). 60 Italian and Greek samples were not different in terms of SERTPR genotypes frequencies (w 2 ¼ 4.3; df ¼ 2; P ¼ 0.1).…”

Section: Resultssupporting

confidence: 92%

“…The gene coding for it has been proposed as a possible candidate for involvement in the pathogenesis of major psychoses. A functional polymorphism in the upstream regulatory region of the gene has been associated with both major depressive and bipolar disorders, [43][44][45] although subsequent studies did not replicate these results. [46][47][48][49][50][51][52][53][54][55][56][57][58] The polymorphism in the upstream is a deletion/insertion (SERTPR) located exactly at the 5 0 -flanking regulatory region of serotonin transporter gene on chromosome 17q11.2.…”

Section: Introductionmentioning

confidence: 99%

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Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

et al. 2004

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We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (X1200 mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome. INTRODUCTIONLithium is an effective prophylactic agent in mood disorders but not all patients equally respond to lithium therapy. Clinical predictors account for less than half of the variance, 1-8 and there are evidences suggesting that genetic factors play a substantial role in lithium prophylaxis effectiveness. [9][10][11][12][13][14][15][16][17][18][19][20] A large number of studies reported an association between prophylactic lithium response and a family history of bipolar disorder, 10,[12][13][14]17 although not unequivocally confirmed. [21][22][23][24][25] Recently, Grof et al 26 reported that lithium response in a sample of relatives of responder probands was 67% compared to 30% in the comparison group.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

et al. 2004

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“…48,59 The 31 papers finally selected reported 43 studies related to the review objective in total since each paper frequently reported several separate studies. In total, 17 population-based studies 9,14,33,34,38,46,50,51,56,60,61,66,[68][69][70] and six family-based studies 12,32,42,53,63,74 were about 5-HTTLPR. A total of 16 population-based studies 27,33,35,38,41,47,[49][50][51]54,56,58,60,61,70,75 and four family-based studies 12,52,57,63 were about the intron 2 VNTR.…”

Section: Resultsmentioning

confidence: 99%

“…51 The remaining studies mentioned that the sample was ethnically homogeneous. 9,14,34,35,49,54,58,61,68,70,75 5-HTTLPR meta-analysis In total, 17 population-based studies comprised 1712 cases (ie 3424 alleles) and 2583 controls, whereas six family-based studies comprised 587 trios. Summaries are shown in the Tables 1 and 2.…”

Section: Resultsmentioning

confidence: 99%

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using metaanalytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies-both population-based and family-based studies-investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P ¼ 0.41 for the 5-HTTLPR and P ¼ 0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P ¼ 0.35 for the 5-HTTLPR and P ¼ 0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT. Keywords: bipolar disorder; serotonin transporter; polymorphisms; genetics; association study; meta-analysis Bipolar disorder (BPD), also known as manic-depressive illness, is a frequent and severe psychiatric disorder with the lifetime prevalence between 1 and 2% in the general population, being equally distributed across sexes. 1 The etiology is unknown although the presence of a complex dysfunction at multiple levels such as neurotransmitter system, prefrontallimbic-subcortical circuit and neuroendocrinological system has been suggested. 2 Family studies have indicated a marked increase in lifetime risk of the illness in first-degree relatives of the proband, varying between five and 10 times that of the general population. 3 Twin studies have shown an increased risk in monozygotic co-twins compared with dizygotic co-twins of a proband with BPD. The risk in monozygotic co-twins has been estimated at 45-75 times that of the general population. 3,4 Adoption studies have also shown that the risk of BPD is greater in biological relatives than in adoptive relatives of the probands. 5 Most of the segregation studies have shown that the inheritance of BPD cannot be explained b...

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“…The 5-HTT has been directly implicated in depression by the finding that brain 5-HTT binding density is reduced in brains and platelets of depressed patients (e.g., Nemeroff et al 1994;Malison et al 1998;Mann et al 2000). Moreover, a number of studies have found an association between genetic variation in the regulatory region of the 5-HTT gene and depression (e.g., Battersby et al 1996; Collier et al 1996a,b;Furlong et al 1998;Rees et al 1997;Menza et al 1999; but see Seretti et al 1999). The 5-HTT is also a major target for many antidepressant drug treatments (Blakely et al 1991;Ramamoorthy et al 1993).…”

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confidence: 99%

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

Holmes

Yang

Murphy

et al. 2002

Neuropsychopharmacology

262

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Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT 5-HTT Ϫ / Ϫ mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT Ϫ / Ϫ mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT Ϫ / Ϫ mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg Antidepressants are thought to normalize the disturbances in monoamine function that occur in affective disorders (Feighner and Boyer 1996;Frazer 1997; Montgomery and Den Boer 2001). While dysfunctions in noradrenergic and dopaminergic systems are putative etiological factors in depression, there is considerable evidence indicating that perturbation of central serotonergic activity is a major etiological component of depression (Willner 1985;Murphy 1990;Maes and Meltzer 1995;Charney 1998 NO . 6 Antidepressant Responses in 5-HTT KO Mice 915 (for reviews see Brown and Linnoila 1990;Owens and Nemeroff 1998;Mann 1999). The serotonin transporter (5-HTT) acts as a key regulator of serotonin signaling. By regulating reuptake of released serotonin, the 5-HTT controls the duration and intensity of serotoninergic activity at the synapse. The 5-HTT has been directly implicated in depression by the finding that brain 5-HTT binding density is reduced in brains and platelets of depressed patients (e.g., Nemeroff et al. 1994;Malison et al. 1998;Mann et al. 2000). Moreover, a number of studies have found an association between genetic variation in the regulatory region of the 5-HTT gene and depression (e.g., Battersby et al. 1996; Collier et al. 1996a,b;Furlong et al. 1998;Rees et al. 1997;Menza et al. 1999; but see Seretti et al. 1999). The 5-HTT is also a major target for many antidepressant drug treatments (Blakely et al. 1991;Ramamoorthy et al. 1993). It is well known that the serotonin reuptake inhibitor (SRI) class of antidepressants increase concentrations of serotonin in the synapse by blocking the serotonin transporter (5-HTT) (Blakely et al. 1991;Ramamoorthy et al. 1993). However, given the time lag between the initial inhibitory effects of antidepressants on the 5-HTT and an observable improvement in sympt...

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Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT)

Cited by 148 publications

References 0 publications

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

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