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A genetic basis for the variable effect of smoking/nicotine on Parkinson’s disease


Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson’s disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 × 10−7 for gene–smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 × 10−11 for nicotine–paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 × 10−10). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.

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We thank the persons with Parkinson's disease and volunteers who participated in the study. We also thank Dr John Nutt for his continued support for this project and Dr Sridar Chittur (Center for Functional Genomics at State University of New York at Albany) for processing the expression arrays. The project was funded by grants from the National Institute of Neurological Disorders and Stroke (R01NS36960 and R01NS067469). Additional support was provided by a Merit Review Award from the Department of Veterans Affairs (1I01BX000531), National Institute of Aging (P30AG08017), Office of Research & Development, Clinical Sciences Research & Development Service, Department of Veteran Affairs, and the Close to the Cure Foundation. Genotyping services were provided by the Center for Inherited Disease Research, which is funded by the National Institutes of Health (HHSN268200782096C).

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Correspondence to H Payami.

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Hill-Burns, E., Singh, N., Ganguly, P. et al. A genetic basis for the variable effect of smoking/nicotine on Parkinson’s disease. Pharmacogenomics J 13, 530–537 (2013).

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  • SV2C
  • nicotine
  • Parkinson’s disease

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