Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia

Anney, Richard; Rees, Mark I.; Bryan, Edward M.; Spurlock, Gillian; Williams, Nigel; Norton, Nadine; Williams, Hywel; Cardno, Alastair G.; Zammit, Stanley; Jones, Susan; Jones, G.; Hoogendoorn, Bastiaan; Smith, Kaye; Hamshere, Marian L.; Coleman, Sharon Louise; Guy, Carol; O'Donovan, Michael Conlon; Buckland, Paul Robert

doi:10.1038/sj.mp.4001003

Cited by 34 publications

(17 citation statements)

References 23 publications

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“…24,25,8,9 In addition, thorough studies on the characterization, mutation detection and association analysis of alternative promoters and 5 0 UTRs of the human DRD3 gene in schizophrenia imply that neither the coding nor the regulatory region of DRD3 plays a major role in predisposition to schizophrenia. 10 On the contrary, the contribution of the A-206G transition to the development of Tardive Dyskinesia (TD) in schizophrenic patients treated with antipsychotics has been maintained unanimously. 26,27 In the present study we observed a marginally nonsignificant excess in the percentages of both homozygote genotypes in the patient group (P ¼ 0.054), although the estimation of the individual OR values of G-206/G-206 and A-206/A-206 genotypes using A-206/G-206 as a genotype baseline risk, revealed statistically significant association for the wild-type homozygotes, (P ¼ 0.016, OR ¼ 1.88, 95% CI ¼ 1.09 -3.26), indicating indirectly a higher risk of this genotype to develop schizophrenic disorder.…”

Section: Discussionmentioning

confidence: 99%

Association between schizophrenia and DRD3 or HTR2 receptor gene variants

Baritaki

Rizos²,

Zafiropoulos

et al. 2004

Eur J Hum Genet

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Schizophrenia is a severe and common psychiatric disorder afflicting 1% of the world population. A role of many neurotransmitter receptors in schizophrenia was suggested by an association with several polymorphisms located in their coding regions. In this study we examined the contribution of the T-102C and A-206G transitions in the 5-HTR2a and DRD3 receptor genes respectively to genetic susceptibility and phenotypic expression of schizophrenia disorder within the Greek population. We determined by PCR and RFLP analysis the genotype for the above polymorphisms in 114 schizophrenic hospitalized individuals and 192 control samples. In contrast to previous reports from large European multicentre studies, which indicate significant correlation between schizophrenia and C-102 allele of the T-102C polymorphism, in this study we observed a statistically significant overall association between the disorder and allele T-102 (Po0.0001, odds ratio (OR) ¼ 2.11, 95% CI ¼ 1.48-3.02). We also found a highly significant excess of the T-102/C-102 and C-102/C-102 genotypes in the normal group (Po0.001). Comparison of the patients with the controls for the DRD3 polymorphism (A-206G transition) showed marginally nonsignificant differences in the genotypic (P ¼ 0.054) and no significance in the allelic (P ¼ 0.163) frequencies. However, the A-206/ A-206 genotype seems to positively contribute to the disorder appearance, when compared to A-206/ G-206 as genotype base line risk (P ¼ 0.016, OR ¼ 1.88, 95% CI ¼ 1.09-3.26). In conclusion, from genetic association analysis of this schizophrenic population, a significant association is clearly determined between the HTR2 genetic polymorphism and the presence of schizophrenic disorder, manifested as increased risk of schizophrenia for carriers of the T-102 allele.

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Section: Discussionmentioning

confidence: 99%

Association between schizophrenia and DRD3 or HTR2 receptor gene variants

Baritaki

Rizos²,

Zafiropoulos

et al. 2004

Eur J Hum Genet

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“…However, the most recent report from the same group that conducted this meta-analysis and contributed to the original report on the DRD3 association, is essentially negative. Anney et al [26] examined 10 novel SNPs, including some in the promoter region of the gene, but found no evidence for associations between schizophrenia and any of these or with the Ser9Gly variant.…”

Section: Functional Candidate Genesmentioning

confidence: 98%

Linkage and association studies of schizophrenia

McGuffin

Tandon²,

Córsico³

2003

Curr Psychiatry Rep

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Recent twin studies confirm that schizophrenia is highly heritable, but attempts to locate and identify genes have proved to be difficult. This is largely because major genes appear to be rare or nonexistent. Instead, genetic liability almost certainly results from the combined effects of multiple susceptibility loci and most studies have been under-equipped to detect such effects. Nevertheless, several regions of the genome have been implicated by more than one linkage study and chromosome 22q has been implicated by linkage and by studies of patients with microdeletions. Recent work attempting to refine regions of interest using linkage dysequilibrium mapping has identified four promising and novel "positional candidates;" they are neuregulin-1 on chromosome 8p-p21, G72 located at chromosome 13q34, dysbindin at 6p22.3, and proline dehydrogenase, which is a gene that maps to chromosome 22q11. In addition, there is renewed interest in a fifth gene, catechol-O-methyltransferase, also on chromosome 22q11.

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“…Like many other psychiatric disorders, schizophrenia is thought to involve the combined effects of multiple genetic components. 1,2 Research, such as linkage analyses and association studies, [3][4][5][6][7][8][9][10][11][12] has not yet identified definitive genes responsible for the disease.…”

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confidence: 99%

Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth

et al. 2003

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Disrupted-In-Schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation that segregated with schizophrenia in a Scottish family. Predicted DISC1 product has no significant homology to other known proteins. Here, we demonstrated the existence of DISC1 protein and identified fasciculation and elongation protein zeta-1 (FEZ1) as an interacting partner of DISC1 by a yeast two-hybrid study. FEZ1 and its nematode homolog are reported to represent a new protein family involved in axonal outgrowth and fasciculation. In cultured hippocampal neurons, DISC1 and FEZ1 colocalized in growth cones. Interactions of these proteins were associated with F-actin. In the course of neuronal differentiation of PC12 cells, upregulation of DISC1/FEZ1 interaction was observed as along with enhanced extension of neurites by overexpression of DISC1. The present study shows that DISC1 participates in neurite outgrowth through its interaction with FEZ1. Recent studies have provided reliable evidence that schizophrenia is a neurodevelopmental disorder. As there is a high level of DISC1 expression in developing rat brain, dysfunction of DISC1 may confer susceptibility to psychiatric illnesses through abnormal development of the nervous system.

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Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia

Cited by 34 publications

References 23 publications

Association between schizophrenia and DRD3 or HTR2 receptor gene variants

Association between schizophrenia and DRD3 or HTR2 receptor gene variants

Linkage and association studies of schizophrenia

Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth

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