An association study of bipolar mood disorder (type I) with the 5-HTTLPR serotonin transporter polymorphism in a human population isolate from Colombia

Ospina‐Duque, Jorge; Duque, Constanza; Carvajal‐Carmona, Luis G.; Ortiz‐Barrientos, Daniel; Soto, Iván; Pineda, Nicolás; Cuartas, Mauricio; Calle, Jorge; López, Carlos A.; Ochoa, Luis F.; García, Jenny; Gómez, Juan Felipe Garcés; Agudelo, Andrés Alonso; Lozano, Maximino; Montoya, Gabriel; Ospina, A.; López, María Cecilia; Gallo, Aurora; Miranda, Ana Lúcia Brenner Barreto; Serna, Lina; Montoya, Patricia; Palácio, Carlos; Bedoya, Gabriel; McCarthy, Mark I.; Reus, Victor I.; Freimer, Nelson B.; Ruiz-Linares, Andrés

doi:10.1016/s0304-3940(00)01464-6

Cited by 76 publications

(44 citation statements)

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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%

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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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Section: Resultsmentioning

confidence: 99%

“…27,33,56 One used an isolated population. 46 One did not mention the ethnicity of the study sample. 51 The remaining studies mentioned that the sample was ethnically homogeneous.…”

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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“…23 Since then, many more groups have examined this gene in other behavioural disorders including anxiety-related traits, suicide, bipolar mood disorder, attention deficit hyperactivity disorder, impulsive aggressive behaviour and psychoticism. [24][25][26][27][28][29] Unfortu- …”

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confidence: 99%

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

et al. 2005

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Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P ¼ 0.002, AH2 P ¼ 0.014), the test of semantic memory (P ¼ 0.010) and general cognitive ability (P ¼ 0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly. Keywords: serotonin transporter; polymorphism; cognition; memory; genes; associationIn an increasingly long-lived population severe cognitive impairment, caused by either the normal ageing process or dementia, is an escalating problem that currently has no effective treatment. Cognitive ability and its rate of decline are highly heritable and both have been shown to predict dementia onset. [1][2][3][4] Of the 13 quantitative trait loci (QTL) currently associated with the level of cognitive ability in normal individuals the most widely reported are located in genes involved in synaptic transmission. 5 These comprise the adrenergic receptor 2A, catechol-O-methyltransferase, dopamine receptor D2, cholinergic muscarinic 2 receptor, brain-derived neurotrophic factor, metabotrophic glutamate receptor 3 and the serotonin receptor 2A. [6][7][8][9][10][11][12][13] To date only the apolipoprotein E e4 allele has been associated with cognitive decline in nondemented individuals and this finding has been challenged. [14][15][16][17][18][19] Serotonin has been shown to play a role in brain development and cognitive functioning. 20,21 There is also a decrease in total brain serotonin with age that may predispose the elderly to depression, dementia and cognitive dysfunction. 22 Despite the importance of serotonin as a modulator of memory and learning the influence of two functional polymorphisms (HTTLPR and VNTR2) in the SLC6A4 gene, which codes for a protein responsible for the reuptake of serotonin, have n...

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“…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. It consists of a 44-bp insertion or deletion involving repeat elements 6 to 8 (from bp À1212 to bp À1255).…”

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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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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An association study of bipolar mood disorder (type I) with the 5-HTTLPR serotonin transporter polymorphism in a human population isolate from Colombia

Cited by 76 publications

References 19 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

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

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

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