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Schizophrenia Bulletin Advance Access published online on March 9, 2009
Schizophrenia Bulletin, doi:10.1093/schbul/sbp005
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© The Author 2009. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Functional Analysis of Upstream Common Polymorphisms of the Dopamine Transporter Gene

Mikhil N. Bamne2, Michael E. Talkowski2,3, Kodavali V. Chowdari2 and Vishwajit L. Nimgaonkar13
2 Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15213
3 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213

1 To whom correspondence should be addressed; Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine and Graduate School of Public Health, Room 441, 3811 O'Hara Street, Pittsburgh, PA 15213; tel: 412-246-6353, 1-877 363 5895, 1-800 994 8182, fax: 412-246-6350, e-mail: nimga{at}pitt.edu

The human dopamine transporter (DAT, SLC6A3) has been extensively investigated because of its potential involvement in neuropsychiatric disorders. The core elements responsible for its transcription have been identified. A regulatory role for certain genomic variants upstream to the core promoter is known. Recently, other single-nucleotide polymorphisms (SNPs) have been identified in this region and are thought to be associated with schizophrenia and bipolar I disorder. Hence, we have investigated the impact of common SNPs in a 2.8-kilobase region flanking the core promoter region (–2.7 to +63 base pair) in the neuroblastoma cell line SH-SY5Y. Haplotypes generated by site-directed mutagenesis revealed varying impact of individual SNPs on promoter activity using dual luciferase assays. In silico analyses also predicted allele-specific binding of transcription factors for some of these SNPs. Though electrophoretic mobility shift assays indicated several factors that appeared to bind to specific sites within this region, allele-specific binding was not detected for any SNP apart from rs3756450. We have thus identified novel putative regulatory domains flanking the core promoter of DAT that merit further investigation.

Keywords: dopamine transporter / single-nucleotide polymorphism / electrophoretic mobility shift assay / reporter assay / schizophrenia / bipolar disorder


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