No association between schizophrenia and polymorphisms within the genes for debrisoquine 4‐hydroxylase (CYP2D6) and the dopamine transporter (DAT)

Daniels, J.; Williams, Julie; Asherson, P.; McGuffin, Peter; Owen, Michael John

doi:10.1002/ajmg.1320600115

Cited by 41 publications

(17 citation statements)

References 13 publications

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“…[13][14][15][16][17] Yet, these studies should be interpreted with caution as they only analysed two or three defective CYP2D6 variant alleles (*3, *4 and/or *10) as causing PM status, and/or used a diverse control group, that is non-psychotics. 17 The differences found in the present study in the allele distribution between schizophrenic patients and healthy volunteers cannot be explained by ethnicity, because both populations were White-Europeans from the same region of Spain.…”

Section: Discussionmentioning

confidence: 99%

“…11 The CYP2D6*10 allele is associated with decreased CYP2D6 activity and is particularly common in Chinese and Japanese populations. 12 Association studies between CYP2D6 and schizophrenia have found no association, [13][14][15][16][17] which can be partly explained by the fact that only two or three defective CYP2D6 alleles (*3, *4 and/or *10) were analysed. However, other studies have shown an under-representation of PMs in schizophrenia patients.…”

Section: Introductionmentioning

confidence: 99%

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Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

et al. 2007

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CYP2D6 has been suggested to be functionally similar to the dopamine transporter. The present study was aimed at analysing the frequency of CYP2D6 alleles and genotype among schizophrenic patients compared to healthy volunteers. CYP2D6 *3, *4, *5, *6, *10 and duplicated alleles were analysed in 128 unselected schizophrenia inpatients (SP) and 142 unrelated white European Spanish healthy volunteers (HV). SP and HV with 42, 2, 1 or 0 CYP2D6 active genes were 4.7, 64.8, 28.1 and 2.3%, and 6.3, 52.1, 33.1 and 8.5%, respectively. The frequency of homozygous for CYP2D6 inactive alleles or poor metabolizers (PMs) was lower (Po0.05) in SP than in HV. Furthermore, the frequency of CYP2D6 inactive alleles was also lower in SP than in HV (16.8 vs 25.7; Po0.05), specifically the CYP2D6*6 allele was not found among patients. The present study shows a lower frequency of PMs in schizophrenic patients than in healthy volunteers supporting the hypothesis of a potential role of CYP2D6 in the vulnerability to schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

et al. 2007

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“…In the context of DAT1 association studies, the most reproducible finding has been the association of a VNTR polymorphism within the 3 0 untranslated region of the gene with ADHD, which has been reported in several populations [Cook et al, 1995;DiMaio et al, 2003]. Several reports, however, have failed to establish a significant association [Daniels et al, 1995;Pean et al, 1995;Georgieva et al, 2002;Hauser et al, 2002] or linkage [Byerley et al, 1993;Persico et al, 1995] with any of the DAT1 3 0 VNTR alleles and schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Association of the dopamine transporter gene (DAT1) core promoter polymorphism −67T variant with schizophrenia

Khodayari

Garshasbi

Fadai

et al. 2004

American J of Med Genetics Pt B

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Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of schizophrenia. The dopamine transporter (DAT1) mediates the active reuptake of dopamine from the synapses and thereby plays a key role in the regulation of the dopaminergic neurotransmission. In this study, we sought to determine the possible association of the DAT1 gene core promoter polymorphism -67A/T with schizophrenia in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 100 patients and 100 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 29%; AT 59%; TT 12% versus the genotype frequencies in the control group: AA 57%; AT 38%; TT 5% [chi2 = 16.54, df = 2, OR = 2.25 (95% CI 1.46-3.45, P < or = 0.0003]. For the first time, these findings provide tentative evidence for the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of schizophrenia at least in the Iranian male population that we studied. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings.

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“…However, most genetic studies investigating differences in SCZ cases and controls of this VNTR polymorphism at SLC6A3 have failed to find an association with the disorder [18][19][20][21][22][23][24][25][26][27][28][29][30] . However, one previous study has reported that the SLC6A3 genotypes in SCZ patients displayed significantly enhanced homozygote (genotypes 9/9 and 10/10) and reduced heterozygote (genotype 9/10) frequencies of the most common genotypes, maybe representing stigmata of assortative mating 31 .…”

Section: Discussionmentioning

confidence: 99%

“…Linkage studies in SCZ pedigrees from Utah 18,19 , Italy 20 , Rouen, France, the Island of La Reunion 21 , Germany 22 , and India 23 have all failed to demonstrate positive linkage of this VNTR to SCZ. Most of the past association studies have also reported no significant evidence for association between this SLC6A3 polymorphism and SCZ [22][23][24][25][26][27][28][29][30] . However, Persico and Macciardi (1997) showed that the SLC6A3 genotypes in SCZ patients displayed significantly enhanced homozygote (genotypes 9/9 and 10/10) and reduced heterozygote (genotype 9/10) frequencies of the most common genotypes when contrasted with controls 31 .…”

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confidence: 99%

Lack of association between VNTR polymorphism of dopamine transporter gene (SLC6A3) and schizophrenia in a Brazilian sample

Cordeiro

Talkowski

Wood

et al. 2004

Arq. Neuro-Psiquiatr.

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-A role of dopaminergic dysfunction has been postulated in the aetiology of schizophrenia. We hypothesized that variations in the dopamine transporter gene (SLC6A3) may be associated with schizophrenia. We conducted case-control and family based analysis on the polymorphic SLC6A3 variable number tandem repeat (VNTR) in a sample of 220 schizophrenic patients, 226 gender and ethnic matched controls, and 49 additional case-parent trios. No differences were found in allelic or genotypic distributions between cases and controls and no significant transmission distortions from heterozygous parents to schizophrenic offspring were detected. Thus, our results do not support an association of the SLC6A3 VNTR with schizophrenia in our sample.KEY WORDS: DAT1, SLC6A3, schizophrenia, genetic polymorphism, genetic association, trios. Ausência de associação entre o polimorfismo VNTR do gene do transportador de dopamina (SLC6A3) e esquizofrenia em uma população brasileiraRESUMO -Genes do sistema dopaminérgico são de escolha para a pesquisa de susceptibilidade para a esquizofrenia. Desse modo, possível contribuição do polimorfismo do gene do transportador de dopamina (SLC6A3) no aumento da vulnerabilidade para a esquizofrenia foi investigada no presente estudo. Analisou-se a distribuição do sítio polimórfico do gene do transportador de dopamina (VNTR) em uma população de 220 pacientes com esquizofrenia (critério diagnóstico: DSM-IV) e comparou-se com a distribuição em uma população controle de 226 indivíduos pareados para sexo e etnia. Nenhuma diferença foi observada na distribuição dos alelos entre casos e controles. O mesmo polimorfismo também foi investigado em uma segunda amostra composta por 49 trios (pais e probando). O resultado também foi negativo. Tais dados não dão suporte para a participação do polimorfismo do gene do transportador de dopamina no aumento de susceptibilidade para esquizofrenia na amostra estudada. PALAVRAS-CHAVE: DAT1, SLC6A3, esquizofrenia, polimorfismo genético, associação genética, trios. Schizophrenia (SCZ) affects some 1% of the general population. Epidemiological studies have indicated a strong genetic component in the pathogenesis of SCZ and heritability estimates as high as 80% have been reported 1 . Pharmacological evidence suggests an involvement of the dopaminergic system as many antipsychotic drugs block dopamine receptors in the brain and are highly effective in treating symptoms of SCZ 2 . Further, amphetamines and cocaine tend to provoke or exarcebate psychotic symptoms in susceptible individuals by preventing dopamine re-uptake 3 . L-DOPA has also been implicated in psychotic symptoms through variable release of dopamine into the synapse 4 . Therefore, genes involved in the dopaminergic system are potential targets for genetic association studies with SCZ 5 .Polymorphisms in dopamine receptors have been widely examined, but the results have been inconclusive [6][7][8][9][10][11][12] . Another possible candidate is the dopamine transporter gene (SLC6A3 or DAT1). The dopamine tran...

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No association between schizophrenia and polymorphisms within the genes for debrisoquine 4‐hydroxylase (CYP2D6) and the dopamine transporter (DAT)

Cited by 41 publications

References 13 publications

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

Association of the dopamine transporter gene (DAT1) core promoter polymorphism −67T variant with schizophrenia

Lack of association between VNTR polymorphism of dopamine transporter gene (SLC6A3) and schizophrenia in a Brazilian sample

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