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Human Molecular Genetics Advance Access published online on December 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi445
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received October 21, 2005
Revised November 30, 2005
Accepted November 30, 2005

Article

Gain of Function Haplotypes in the Vesicular Monoamine Transporter Promoter are Protective for Parkinson Disease in Women

Charles E. Glatt 1 *, Angelika D. Wahner 2, Daniel J. White 3, Andres Ruiz-Linares 3, and Beate Ritz 2

1 Department of Psychiatry, Weill Medical College of Cornell University, New York, NY, 10028, USA; Department of Psychiatry, Weill Medical College of Cornell University, Rm. LC907A, Box 244, 1300 York Ave., New York, NY, 10021
2 Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA 90095, USA
3 The Galton Laboratory, University College London, UK

* To whom correspondence should be addressed.
Charles E. Glatt, E-mail: ceg2004{at}med.cornell.edu


  Abstract

The vesicular monoamine transporter can protect against toxins that induce an acute Parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) that affect its quantitative expression might therefore serve as genetic risk factors for Parkinson Disease. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain of function haplotypes that display significantly increased transcriptional activity from the reference element. These gain of function haplotypes were tested for association with Parkinson Disease and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for Parkinson Disease.


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