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Human Molecular Genetics Advance Access originally published online on November 27, 2007
Human Molecular Genetics 2008 17(5):747-758; doi:10.1093/hmg/ddm347
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A network of dopaminergic gene variations implicated as risk factors for schizophrenia

Michael E. Talkowski1,3, George Kirov4, Mikhil Bamne1, Lyudmila Georgieva4, Gonzalo Torres2, Hader Mansour1, Kodavali V. Chowdari1, Vihra Milanova5, Joel Wood1, Lora McClain1, Konasale Prasad1, Brian Shirts3, Jianping Zhang6, Michael C. O’Donovan4, Michael J. Owen4, Bernie Devlin1,3 and Vishwajit L. Nimgaonkar1,3,*

1 Department of Psychiatry and 2 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 3 Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA 4 Department of Psychological Medicine, Cardiff University, Heath Park, Cardiff, UK 5 Department of Psychiatry, Medical University, Sofia, Bulgaria and 6 Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School, Mayo Clinic, Rochester, MN, USA

* To whom correspondence should be addressed at: Department of Psychiatry, University of Pittsburgh School of Medicine, WPIC, Office 444, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel: +1 4122466353; Fax: +1 4122466350; Email: nimga{at}pitt.edu

Received September 15, 2007; Accepted November 26, 2007

We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p ≤ 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (pjoint < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p ≤ 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluasted rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.


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