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, 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 release of dopamine through synaptic vesicles, and PD is caused by 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 suggest SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.