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Human Molecular Genetics Advance Access published online on November 27, 2007
Human Molecular Genetics, 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. Talkowski2,1, George Kirov4, Mikhil Bamne1, Lyudmila Georgieva4, Gonzalo Torres3, Hader Mansour1, Kodavali V. Chowdari1, Vihra Milanova5, Joel Wood1, Lora McClain1, Konasale Prasad1, Brian Shirts2, Jianping Zhang6, Michael C. O'Donovan4, Michael J. Owen4, Bernie Devlin1,2 and Vishwajit L. Nimgaonkar1,2,*

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

* Corresponding Author: Dr. Vishwajit L. Nimgaonkar, M.D., Ph.D. Professor Departments of Psychiatry and Human Genetics, University of Pittsburgh, School of Medicine and Graduate, School of Public Health WPIC, Office 444 3811 O'Hara St Pittsburgh, PA 15213 Tel: 412-246-6353 Fax: 412-246-6350 Email: nimga{at}pitt.edu

Received September 15, 2007; Revised November 26, 2007; Accepted November 26, 2007

We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia.

Stage I (screening): Eighteen dopamine-related genes were analyzed 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).

Stage II (SNP coverage and epistasis): To comprehensively evaluate these four genes, 68 SNPs were genotyped in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < 0.05). We tested for epistasis between pairs of SNPs providing main effects and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3.

Stage III (confirmation): Sixty-five SNPs were genotyped in 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were over-transmitted 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 7 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).

Stage IV (function): We tested rs464049 and rs3756450 for functional effects and found significant allele specific differences at rs3756450 using EMSA and dual-luciferase promoter assays.

Conclusions: Our data suggest a network of dopaminergic polymorphisms increase risk for schizophrenia.


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