Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings

Hranilović, Dubravka; Schwab, Sibylle G.; Jernej, Branimir; Knapp, Michael; Lerer, Bernard; Albus, Margot; Rietschel, Marcella; Kanyas, Kyra; Borrmann, M.; Lichtermann, Dirk; Maier, Wolfgang; Wildenauer, Dieter B.

doi:10.1038/sj.mp.4000599

Cited by 49 publications

(25 citation statements)

References 40 publications

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“…A marginal association was also observed with the 5-HTT VNTR polymorphism: an excess of the 12 repeat allele was observed in patients in comparison with controls (P = 0.05). This finding had also been found in Chinese and European schizophrenic patients [Hranilovic et al, 2000;Tsai et al, 2002], patients suffering schizoparanoid disorders [Kaiser et al, 2001] and bipolar patients . Although our results would not be statistically significant if Bonferoni corrections were applied, the coincidence with previous findings strengthens the hypothesis of a minor contribution of 5-HTT polymorphisms in the aetiology of psychotic disorders.…”

Section: Discussionsupporting

confidence: 69%

“…Polymorphisms in the gene coding for 5-HT2A receptors have been related to schizophrenia, bipolar disorder and psychotic symptomatology [Inayama et al, 1996;Williams et al, 1996;Du et al, 1999;Joober et al, 1999;Nacmias et al, 2001;Araga and Narasu, 2002;Bonnier et al, 2002;Golimbet et al, 2002]. Genetic variants of the serotonin transporter (5-HTT) have also been associated with psychotic disorders Malhotra et al, 1998;Hranilovic et al, 2000;Kaiser et al, 2001;Tsai et al, 2002]. However, there is also a wealth of publications that fail to support these findings [Gutierrez et al, 1995;Rao et al, 1998;Shinkai et al, 1998;He et al, 1999;Oliveira et al, 2000;Haider and Zahid, 2002;Serretti et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

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Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Mata¹,

Arranz²,

Patiño

et al. 2003

American J of Med Genetics Pt B

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There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (-1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P≤0.05) indicating a minor contribution to psychosis of genetic alterations in this gene.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Mata¹,

Arranz²,

Patiño

et al. 2003

American J of Med Genetics Pt B

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“…In the serotonin transporter gene, a variable number of tandem repeats (VNTR) are located approximately 1 kb upstream from the transcription initiation site, and the polymorphic length of the VNTR is associated with anxiety-related traits 17 and other diseases including schizophrenia. 18 The monoamine oxidase (MAOA) gene contains a VNTR located 1-1.2 kb upstream of the transcription initiation site. 19 This VNTR consists of a 30-bp repeated sequence present as either 3, 3.5, 4, or 5 copies.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

Identification of a compound short tandem repeat stretch in the 5′-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia

et al. 2001

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The cholecystokinin gene (CCK) is thought to play a role in the pathogenesis of both panic disorder 1-4 and schizophrenia. 5 In this study, we have extended the 5Ј-upstream sequence of the CCK gene, and identified a compound short tandem repeat (STR), located approximately −2.2 to −1.8 kb from the cap site. This STR was found to be polymorphic with ten different allele lengths. Case-control studies using 73 panic patients, 305 schizophrenics and 252 controls showed a significant allelic association with panic disorder (P = 0.025), but not with schizophrenia. Dividing the STR alleles into three classes according to length, Long (L), Medium (M) and Short (S), produced strong genotypic (MM) (nominal P = 0.0014) and allelic (M) (nominal P = 0.0079) associations with panic disorder. Screening the newly extended promoter region detected not only the previously identified −36CϾT and −188AϾG single nucleotide polymorphisms (SNPs) but a new rare SNP, −345GϾC. Neither of the former two SNPs showed significant association with either panic disorder or schizophrenia. Haplotypic distributions of the STR and SNPs −188 and −36 were significantly different between panic samples and controls (P = 0.0003). These findings suggest that the novel STR or a nearby variant may confer susceptibility to the development of panic disorder. Molecular Psychiatry (2001) 6, 465-470. Panic disorder is a common and genetically complex mental illness, characterized by recurrent and unexpected panic attacks. It exhibits a lifetime prevalence rate of between 1.2/100 to 2.4/100 in the general population. 6 Family studies have consistently shown a higher prevalence ranging from between 7.7% to 20.5% in first-degree relatives of probands. 6 Twin studies have shown concordance rates of 25% for MZ twins and 10% for DZ twins, 7 suggesting a genetic component in the development of this disease.The carboxy terminal tetrapeptide of CCK (CCK-4), expressed in the brain, is thought to act as a neurotransmitter and/or neuromodulator. It provokes panic attacks in subjects with panic disorder and normal controls, 1,2 with panic disorder patients having a higher sensitivity to CCK-4 than controls. 3 The panicogenic effect of CCK-4 is inhibited by antagonists of the CCK B receptor 4 which constitutes a large proportion of the CCK receptors in the human brain. 8 These findings have intensified research into elucidating the role of CCK in panic disorder.CCK-like peptides, mainly the carboxy terminal octapeptide of CCK (CCK-8), co-localize with dopamine in mesolimbic dopaminergic neurons. 9 In humans, CCK-8 is reported to have an anti-psychotic effect, 5 inferring a possible role in the pathology of schizophrenia.Two groups simultaneously reported a single nucleotide polymorphism (SNP), −36CϾT in the 5Ј-upstream region of the CCK gene. 10,11 Wang et al 10 showed that the −36T allele was weakly associated with subjects manifesting panic attacks (P Ͻ 0.05) but not with panic disorder. In a case-control study of schizophrenia samples, Bowen et al 11 found no associati...

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“…[14][15][16][17][18][19][20][21] A possible reason for conflicting results is the use of psychiatric diagnoses which do not guarantee biological homogeneity.…”

mentioning

confidence: 99%

“…13 The gene also proved to be associated or showed conflicting evidence with a number of other conditions, like anxiety-related traits in normals and in depressed patients, seasonal affective disorder, anxiety disorders, autism, severe alcoholism, suicidal behavior, psychotic symptomatology in neurolepticfree schizophrenics and schizophrenia. [14][15][16][17][18][19][20][21] A possible reason for conflicting results is the use of psychiatric diagnoses which do not guarantee biological homogeneity. 22 Diagnostic categories contain a high degree of heterogeneity (eg presence of delusional features, anxiety, melancholic features, variable time course and drug response), therefore genetic studies based on diagnostic criteria may furnish biased results based on a different rate of subgroup populations.…”

mentioning

confidence: 99%

Serotonin transporter gene (5-HTTLPR) and major psychoses

et al. 2002

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Serotoninergic neurotransmitter systems have been implicated in the pathogenesis of major psychoses. A functional polymorphism (5-HTTLPR) in the upstream regulatory region of the gene (SLC6A4) has been associated with a number of psychiatric disturbances, but conflicting replication followed. The aim of this study was to investigate the possibility that the 5-HTTLPR might be associated with major psychoses. One thousand, eight hundred and twenty inpatients (789 bipolars, 667 major depressives, 66 delusionals, 261 schizophrenics, 37 psychotics not otherwise specified-NOS) and 457 control subjects were included in this study. A subsample of 1235 patients (523 bipolars, 359 major depressives, 259 schizophrenics, 66 delusionals, 28 psychotic NOS) were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic illness (OPCRIT) checklist. The subjects were also typed for 5-HTTLPR variants using PCR techniques. 5-HTTLPR allele frequencies were not significantly different between controls and bipolars, major depressives, schizophrenics, delusionals and psychotic NOS; genotype analysis also did not show any association. The analysis of symptomatology did not show significant differences. Consideration of possible stratification factors such as sex and age of onset did not significantly influence results. 5-HTTLPR variants are not therefore a liability factor for major psychoses or for major psychoses symptomatology. Molecular Psychiatry ( The serotonin transporter is the major determinant of serotonin inactivation following release at synapses and it is the site of action of most antidepressants. The gene coding for the serotonin transporter (SLC6A4) has been therefore proposed as a possible candidate for involvement in the pathogenesis of major psychoses. The primary structure of the serotonin transporter gene did not prove to be associated with the diagnosis of mood disorders, 1 however, a polymorphic region containing a 17-bp variable number of tandem repeat (VNTR) in the second intron was associated with major depressive disorder 2-4 and a functional polymorphism in the upstream regulatory region of the gene has been associated with both major depressive and bipolar disorders, 5-7 although subsequent studies did not replicate these results. [8][9][10][11][12] The polymorphism in the upstream is a 44-bp deletion/insertion (5-HTTLPR) located exactly at the 5Ј-flanking regulatory region of the serotonin transporter gene on chromosome 17q11.2. In vitro studies evidenced that the basal activity of the long (l) variant was more than twice that of the short (s) form of the 5-HTTLPR, suggesting that serotonin transporter gene transcription is modulated by variants of the 5-HTTLPR with the s allele corresponding to low serotonin uptake activity. 13The gene also proved to be associated or showed conflicting evidence with a number of other conditions, like anxiety-related traits in normals and in depressed patients, seasonal affective disorder, anxiety disorders, autism, severe alcoholism, suic...

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Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings

Cited by 49 publications

References 40 publications

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Identification of a compound short tandem repeat stretch in the 5′-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia

Serotonin transporter gene (5-HTTLPR) and major psychoses

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