Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia

Hawi, Ziarih; McCabe, U; Straub, Richard E.; O'Neill, F. Anthony; Kendler, Kenneth S.; Walsh, Dermot; Gill, Michael

doi:10.1038/sj.mp.4000362

Cited by 32 publications

(14 citation statements)

References 35 publications

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“…A number of associations have been reported with this approach, but replication and interpretation of findings have proved problematic. 2,[22][23][24][25] The recent discovery of trinucleotide repeat expansion has led to a third approach: a search for candidate genes with repeat expansions, a genetic hypothesis of etiology. [26][27][28][29] We review the currently known trinucleotide repeat diseases and the ratio-nale for the hypothesis that repeat expansions may contribute to the genetic etiology of psychiatric disorders.…”

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Trinucleotide Repeat Expansion and Neuropsychiatric Disease

Margolis¹,

McInnis²,

Rosenblatt³

et al. 1999

Arch Gen Psychiatry

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Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g., CCG CCG CCG CCG CCG) within a region of DNA, a not uncommon motif in the genome of humans and other species. In 1991, a new type of genetic mutation was discovered, known as a dynamic or expansion mutation, in which the number of triplets in a repeat increases and the length becomes unstable. During the past decade, nearly 20 diseases-including Huntington disease, 2 forms of the fragile X syndrome, and myotonic dystrophy-caused by trinucleotide repeat expansions have been identified. The unstable nature of the expanded repeat leads to remarkable patterns of inheritance in these diseases, distinctly at odds with traditional notions of mendelian genetics. We review the clinical and genetic features of these disorders, with a particular emphasis on their psychiatric manifestations. We also critically examine the hypothesis that expansion mutations may have an etiologic role in psychiatric diseases such as bipolar disorder, schizophrenia, and autism.

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confidence: 99%

Trinucleotide Repeat Expansion and Neuropsychiatric Disease

Margolis¹,

McInnis²,

Rosenblatt³

et al. 1999

Arch Gen Psychiatry

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“…4 Contemporaneously, with the Williams et al 3 metaanalysis, a large population-based study found no evidence for association of schizophrenia with DRD3. 5 Subsequently, Krebs et al 6 found an association of homozygosity with substance abuse in a small sample of schizophrenia patients and Duaux et al 7 in nonschizophrenic opiate abusers.…”

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confidence: 99%

Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia

Segman¹,

Neeman²,

Heresco-Levy

et al. 1999

Mol Psychiatry

140

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Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3 gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant ( The dopamine D3 receptor gene (DRD3) has been a focus of intense interest in psychiatric genetics for a number of years, primarily in relation to schizophrenia. This interest has not waned in spite of a discouraging disparity in the results obtained. The human DRD3 gene was localized to 3q13.3 by in situ hybridization.1 A polymorphic site in exon 1 of DRD3 gives rise to a serine to glycine substitution in the N terminal extracellular domain of the receptor protein. This creates a BalI (MscI) restriction enzyme site.2 Numerous groups have examined linkage and association of schizophrenia with DRD3. Linkage studies have been uniformly negative. Over 30 studies (mostly population-but also family-based) were included by Williams et al 3 in a meta-analysis that yielded evidence for a modest association with homozygosity for either Correspondence: Professor B Lerer,

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“…Há um nú-mero ainda maior de trabalhos da literatura que não confirmam esse achado [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] . É importante lembrar a existência de um viés de publicação para os trabalhos com resultados positivos.…”

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“…O primeiro estudo de associação entre o polimorfismo alélico serina-9-glicina no gene do receptor D3 mostrou um excesso de homozigose (alelos iguais) quando comparados pacientes com esquizofrenia e controles (p=0,0001), em uma população combinada de caucasianos da França e País de Gales 6 . Estudos posteriores realizados em populações caucasianas [7][8][9][10][11][12][13][14][15][16] e asiáticas [17][18][19][20][21][22] tentaram replicar esse achado, porém sem sucesso. Por outro lado, Shaikh et al 23 e Spurlock et al 24 , em estudo multicêntrico europeu (European Multicentre Association Study of Schizophrenia), encontraram associação entre o polimorfismo alélico em questão e esquizofrenia.…”

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Estudo de associação entre o polimorfismo serina-9-glicina do receptor dopaminérgico D3 e esquizofrenia

Júnior

Junqueira

Vallada

2001

Arq. Neuro-Psiquiatr.

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A hipótese dopaminérgica envolvida na fisiopatologia da esquizofrenia vem do fato dos antipsicóticos exercerem sua ação bloqueando os receptores de dopamina. Os receptores dopaminérgicos do tipo D2 foram os primeiros a serem reconhecidos como alvos dos antipsicóticos clássicos RESUMO -Duas abordagens genético-moleculares foram realizadas para investigar a possível associação entre o polimorfismo serina-9-glicina no receptor dopaminérgico D3 e esquizofrenia. Na primeira análise, um grupo de 141 pacientes com esquizofrenia foi comparado a um grupo-controle de 189 indivíduos pareado para sexo e origem étnica. No outro estudo, foi realizada análise de 35 trios (pai e mãe não afetados e paciente com esquizofrenia). Os resultados desses estudos não apresentaram associação alélica ou genotípica estatisticamente significante com esquizofrenia. Pode-se concluir que o polimorfismo serina-9-glicina no receptor dopaminérgico D3 não é um fator de risco para desenvolver esquizofrenia na população estudada. PALAVRAS-CHAVE: receptor dopaminérgico D3, polimorfismo genético, associação genética, esquizofrenia. Study of association between the ser-9-gly polymorphism of the D3 dopaminergic receptor and schizophreniaABSTRACT -Two molecular genetic studies were undertaken to investigate the association between a ser-9-gly polymorphism in the dopamine D3 receptor gene and schizophrenia. The first study analysed 141 schizophrenic patients and 189 matched controls. In addition, an haplotype relative risk study was performed using 35 trios (mother, father, affected offspring). No allelic or genotype association was found in both studies. We conclude that this D3 polymorphism is not a risk factor for schizophrenia in our sample.KEY WORDS: dopamine D3 receptor, genetic polymorphism, genetic association, schizophrenia.rações cognitivas e afetivas presentes em pacientes com esquizofrenia estão relacionadas a disfunções nesse sistema. Assim, tal receptor surge como um dos candidatos para desempenhar papel importante na fisiopatologia da esquizofrenia 4 . Estudos genéticos recentes envolvendo o receptor D3 têm focado uma mudança de aminoácidos que ocorre em sua porção extracelular 5 . Uma mudança nucleotídica de alanina (A) por guanina (G) resulta em substituição de aminoácido (serina por glicina) na posição 9 da proteína (receptor D3). Não há evidências de que esse polimorfismo do receptor D3 afete a ação de drogas antipsicóticas, nem o processo de transdução, porém tal alteração poderia influenciar sua inserção na membrana neuronal 5 . O primeiro estudo de associação entre o polimorfismo alélico serina-9-glicina no gene do receptor D3 mostrou um excesso de homozigose (alelos iguais)

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Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia

Cited by 32 publications

References 35 publications

Trinucleotide Repeat Expansion and Neuropsychiatric Disease

Trinucleotide Repeat Expansion and Neuropsychiatric Disease

Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia

Estudo de associação entre o polimorfismo serina-9-glicina do receptor dopaminérgico D3 e esquizofrenia

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