Polymorphism in serotonin transporter gene associated with susceptibility to major depression

Ogilvie, Alan D.; Battersby, S.; Fink, George; Harmar, Anthony J.; Goodwin, G M; Bubb, Vivien J.; Smith, Colin

doi:10.1016/s0140-6736(96)90079-3

Cited by 490 publications

(329 citation statements)

References 12 publications

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“…Four of these 24 papers contained the same data. 39,44,62,67 Two were about mental disorders other than BPD. 13,71 Three were not association studies.…”

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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“…Four of these 24 papers contained the same data. 39,44,62,67 Two were about mental disorders other than BPD. 13,71 Three were not association studies.…”

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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“…Defects in the attenuation mechanisms result in the uncontrolled stimulation of cells, which may lead to disease. For example, abnormalities in the 5-hydroxytryptamine transporter may be associated with chronic depression [233], and point mutations of the receptors for thyrotropin hormone and luteinizing hormone which result in constitutive activity of the receptors in the absence of ligand are associated with thyroid adenoma and a form of male precocious puberty respectively [234,235]. From a therapeutic standpoint, over half of all medicines used today exert their effects through signalling pathways that involve G-proteins.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Böhm

Grady

Bunnett

1997

Biochemical Journal

477

322

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The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and downregulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from

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“…In keeping with: (i) the compelling and extensive evidence for central 5-hydroxytryptamine (5-HT, serotonin) playing a role in mood disorders; and (ii) the key role of the 5-HT transporter, which, by allowing high-affinity reuptake of 5-HT into serotonergic neurones, regulates 5-HT neurotransmission (Amara and Kuhar 1993), the findings that allelic variations in (Collier et al 1996a;Ogilvie et al 1996) or nearby (i.e., promoter region) (Lesch et al 1996;Collier et al 1996b) the 5-HT transporter gene may have weaken, but significant impacts on affective and anxiety disorders are unsurprising. Moreover, because polymorphism of disease-related genes may also be predictive of drug response (Kleyn and Vesell 1998), it is then not a surprise that the polymorphism within the promoter region of the 5-HT transporter gene leads to a genetic variability of the antidepressant response to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Smeraldi et al 1998).…”

mentioning

confidence: 93%

Serotonin Reuptake Inhibition by Citalopram in Rat Strains Differing for Their Emotionality

Pollier

Sarre

Aguerre

et al. 2000

Neuropsychopharmacology

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Polymorphism in serotonin transporter gene associated with susceptibility to major depression

Cited by 490 publications

References 12 publications

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

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

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Serotonin Reuptake Inhibition by Citalopram in Rat Strains Differing for Their Emotionality

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