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

Abstract

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.

Figure 1. Drosophila: Effects of paraquat and nicotine on survival

Nicotine improved survival of paraquat-treated flies in a dose-dependent manner. Each treatment combination was started with 420 flies. Survival Curves were plotted using Kaplan Meier survival analysis, and differences between survival curves were calculated using log rank statistics (P=4×10^-30).

Figure 2. Drosophila: Effects of paraquat and nicotine on gene expression

CG14691 gene expression was increased significantly (P=5×10^-8) in response to paraquat and restored to normal with co-treatment with nicotine (paraquat-nicotine interaction P=2×10^-11).

Figure 3. Human: Genome-wide SNP*smoking interaction study

(A) Manhattan plot of -log₁₀(P) values for interaction tested between 811 597 genotyped SNPs and smoking. The strongest signal came from SNPs in two closely linked haploblocks in SV2C on chromosome 5. The best P for any SNP was 2×10^-6 (Black dots). The region contained two independent signals, which when considered together in an additive model, yielded P=1×10^-7 (the red dot was added manually to the Manhattan plot to depict the two-SNP effect). (B) Quantile-quantile plot of SNP*smoking interaction P values. Black: full data. Red: excluding SV2C region.

Figure 4. Human: Linkage disequilibrium in SV2C region

Genotyped SNPs that achieved P_Interaction < 10^-3 for SNP*smoking interaction in the SV2C region were tested for LD; the numbers in the grid represent the correlation (r²) between each pair of SNPs. Although there appear to be three haploblocks, the SNP in the far-right block (rs183766 shown in grey box) did not have an effect independent of the other blocks. Signals from the other two haploblocks (rs30196 and rs10214163 shown in black boxes) appeared to be independent and additive, as indicated by persistent significance of one when conditioned on the more significant one. In line with this evidence for independent effects, joint consideration of genotypes at rs30196 and rs10214163 improved significance level for interaction with smoking to P=1×10^-7.