Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders

Manki, Hiroshi; Kanba, Shigenobu; Muramatsu, Taro; Higuchi, Susumu; Suzuki, Eiji; Matsushita, Satoru; Ono, Yutaka; Chiba, Hiromi; Shintani, Futoshi; Nakamura, Makoto; Yagi, Gohei

doi:10.1016/0165-0327(96)00035-3

Cited by 95 publications

(67 citation statements)

References 30 publications

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“…We also noted such an increase, but it was not statistically significant. The lack of association of TPH with unipolar depression in the present study is in accordance with the results of Furlong et al 11 Manki et al 12 reported an association between the DRD4 alleles and major depression in Japanese subjects, with a decrease in allele 4 and an increase in allele 5 in the patient population. Oruc et al 13 found no association of recurrent unipolar depression with DRD4 alleles in a Croatian population.…”

supporting

confidence: 82%

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

et al. 1999

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Keywords: major depressive disorder (MDD); tryptophan hydroxylase (TPH); serotonin transporter promoter region (5-HTTLPR); serotonin receptor 2A (HTR2A); serotonin receptor 2C (HTR2C); catechol-O-methyl transferase (COMT); dopamine D4 receptor (DRD4); dopamine transporter (DAT1)Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%. 1 The importance of the genetic component is well accepted, 2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.Pharmacological studies have suggested that MDD is associated with an impairment of brain neurotransmitters. The role of serotonin (5-HT), which is based mainly on the efficacy of selective and nonselective 5-HT reuptake inhibitors in the treatment of MDD, was reviewed by Maes and Meltzer. 3 Dopamine (DA), has also been implicated in the pathophysiology of mood disorders and hypoactivity of the mesolimbic DA pathway may be connected to depressive symptoms. 4 Thus, genes that control the brain 5-HT and DA pathways seem to be good candidates for mediating genetic susceptibility to MDD.Association of polymorphisms in seven genes from the serotonergic and dopaminergic pathways was studied in 102 unipolar patients and 172 healthy control subjects. The patient population was subdivided according to ethnic origin (63 Ashkenazi and 39 nonAshkenazi Jews) and compared to the corresponding group of mentally healthy controls. The distribution of genotypes and alleles in the different populations is shown in Table 1. Comparison of healthy individuals of Ashkenazi and non-Ashkenazi origin revealed that although frequencies of genotypes and alleles showed some differences, they did not reach statistical significance. Nevertheless, in order to avoid possible errors caused by population stratifications we compared the patients with their ethnic counterparts.When unipolar MDD patients were compared to healthy controls of the same ethnic origin (Table 1), the distribution of genotypes and alleles of the seven polymorphisms studied (TPH, HTR2A, HTR2C, 5-HTTLPR, DAT1, DRD4 and COMT) did not show statistically significant differences.Molecular genetic studies in mood disorders performed thus far, have focus...

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supporting

confidence: 82%

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

et al. 1999

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“…However, this finding was not replicated in other Caucasian [139,143,148,149,[169][170][171][172] or an Asian study [157] using independent samples. The rarity of the STin2.9 allele (below 1%) means that the risk attributable to this allele is small.…”

Section: Discussionmentioning

confidence: 50%

“…A 48 base pairs repeat in exon 3 of DRD4 was associated with the potency of inhibition of cAMP formation by dopamine [138]. The DRD4 48 base pairs repeat in the exon 3 was significantly associated with major depression while the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms were not [139]. These polymorphisms may be hypothesized to influence major depressive disorder.…”

Section: Genetic Epidemiologymentioning

confidence: 90%

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Molecular epidemiology of major depressive disorder

Kiyohara

Yoshimasu

2009

Environ Health Prev Med

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Major depressive disorder causes significant morbidity, affecting people's ability to work, function in relationships, and engage in social activities. Moreover, major depressive disorder increases the risk of suicidal ideation, attempted suicide and death by completed suicide. There is evidence that chronic stress can cause major depressive disorder. As for genetic factors, only minor susceptibility genes have been reliably identified. The serotonin system provides a logical source of susceptibility genes for depression, because this system is the target of selective serotonin reuptake-inhibitor drugs that are effective in treating depression. The 5-hydroxytryptamine (serotonin) transporter (5-HTT) has received particular attention because it is involved in the reuptake of serotonin at brain synapses. One common polymorphic variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which affects the promoter of the 5-HTT gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain. The authors discussed the relationship between genetic polymorphisms and major depressive disorder, with special emphasis on the 5-HTTTLPR polymorphism. As the 5-HTTLPR polymorphism was significantly associated with an increased risk of major depressive disorder, the 5-HTT gene may be a candidate for a major depressive disorder susceptibility gene. As major depressive disorder is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for major depressive disorder. Hopefully, in the future we will be able to screen for major depressive disorder susceptibility by using specific biomarkers.

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“…However, in linkage studies, major depression has usually been included together with bipolar disorders into a broad definition of affective illnesses. There have been few recent attempts to perform association analyses exclusively on unipolar disorder cases, 12,13 while linkage studies on families with unipolar depression have been attempted only by one group during the 70s and 80s. 14,15 On the other hand, many linkage studies performed during the last 20 years on families with bipolar disorders have contributed to a long list of chromosomal regions with evidence for linkage to bipolar dis-orders.…”

Section: Introductionmentioning

confidence: 99%

Linkage analysis of candidate loci in families with recurrent major depression

et al. 1998

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Recurrent major depression, RMD, is characterized by the occurrence of depressive episodes in the absence of mania and/or hypomania. In linkage studies, RMD (or, in general, unipolar depression) are frequently grouped together with bipolar illnesses into a broad definition of affective disorders. However, twin studies suggest that RMD and bipolar disorders might have different genetic determinants. The objective of this study was to test a set of families with RMD for linkage to chromosomes that have been recently proposed to contain susceptibility loci for bipolar disorders: chromosomes 16, 18, 21 and the short arm of chromosome 4. We analysed five large families from the northern part of Sweden ascertained through a proband with RMD and containing several patients with RMD. For the genetic analysis, we included only severely affected individuals (those who had at least three episodes that required medical treatment) to increase the chances of finding a larger degree of genetic determination. The genetic model led to a total disease prevalence of 5% in females and 3% in males. We did not find significant evidence for linkage to any of the candidate chromosomes in the combined family set. Only one of the families showed a slight indication for linkage with markers from the pericentromeric region of chromosome 18. A genome scan analysis on an extended collaborative family material with severely affected individuals with RMD should be performed to evaluate whether RMD and bipolar disorders have a different genetic etiology.

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Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders

Cited by 95 publications

References 30 publications

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

Molecular epidemiology of major depressive disorder

Linkage analysis of candidate loci in families with recurrent major depression

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