title: Characterisation, mutation detection, and association analysis of alternative promoters and 5' UTRs of the human dopamine D3 receptor gene in schizophrenia.
abstract: The dopamine D(3) receptor gene (DRD3) is a candidate for a number of psychiatric conditions including schizophrenia, bipolar disorder and alcohol and drug abuse. Previous studies have reported associations between polymorphisms in DRD3 and these disorders, but these findings may have reflected linkage disequilibrium with pathogenic variants that are further upstream. We have isolated and sequenced approximately 9 kb of genomic sequence upstream of the human DRD3 translational start site. Using 5' RACE, we have identified within this region three additional exons and two putative promoter regions which show promoter activity in three different cell lines. A 5' UTR identified only in lymphoblasts is spread over three exons and is 353 bp long. A second 5' UTR, found in adult and fetal brain, lymphocytes, kidney and placenta is spread over two exons and is 516 bp long. A 260-bp sequence within this 9 kb corresponds to a previously reported EST, but corresponding mRNA could not be found in the tissues above. The EST, 5' UTRs and putative promoter regions have been analysed for polymorphisms, revealing 10 single nucleotide polymorphisms, seven of which were tested for association in a large sample of unrelated patients with schizophrenia and matched controls. No associations were observed with schizophrenia. In addition we failed to replicate previous findings of association with homozygosity of the Ser9Gly variant. The results from this study imply that neither the coding nor the regulatory region of DRD3 plays a major role in predisposition to schizophrenia.
authors.affiliation: Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Anney
authors.forename: M I
authors.initials: MI
authors.lastname: Rees
authors.forename: E
authors.initials: E
authors.lastname: Bryan
authors.forename: G
authors.initials: G
authors.lastname: Spurlock
authors.forename: N
authors.initials: N
authors.lastname: Williams
authors.forename: N
authors.initials: N
authors.lastname: Norton
authors.forename: H
authors.initials: H
authors.lastname: Williams
authors.forename: A
authors.initials: A
authors.lastname: Cardno
authors.forename: S
authors.initials: S
authors.lastname: Zammit
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.forename: G
authors.initials: G
authors.lastname: Jones
authors.forename: B
authors.initials: B
authors.lastname: Hoogendoorn
authors.forename: K
authors.initials: K
authors.lastname: Smith
authors.forename: M L
authors.initials: ML
authors.lastname: Hamshere
authors.forename: S
authors.initials: S
authors.lastname: Coleman
authors.forename: C
authors.initials: C
authors.lastname: Guy
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.forename: P R
authors.initials: PR
authors.lastname: Buckland
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050637:Receptors, Dopamine D3; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D017931:DNA Primers; C493593:DRD3 protein, human; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3