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

• Published in: The pharmacogenomics journal Vol. 13; no. 6; pp. 530 - 537
• Main Authors: Hill-Burns, E M, Singh, N, Ganguly, P, Hamza, T H, Montimurro, J, Kay, D M, Yearout, D, Sheehan, P, Frodey, K, Mclear, J A, Feany, M B, Hanes, S D, Wolfgang, W J, Zabetian, C P, Factor, S A, Payami, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2013; Nature Publishing Group
• Subjects: 631/208/212/1728; 692/699/375/365/1718; Animals; Biomedical and Life Sciences; Biomedicine; Cigarette smoking; Clinical trials; Complications and side effects; Dopamine; Dopamine - metabolism; Drosophila; Gene Expression; Gene-Environment Interaction; Genetic aspects; Genetic variation; Genome-Wide Association Study; Genomes; Genotypes; Human Genetics; Humans; Insects; Models, Biological; Movement disorders; Neurodegenerative diseases; Nicotine; Nicotine - adverse effects; Oncology; original-article; Paraquat; Parkinson Disease - etiology; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Pharmacogenomics; Pharmacotherapy; Physiological aspects; Psychopharmacology; Risk factors; Smoking; Smoking - adverse effects; Substantia nigra; Synaptic vesicles; United States; nicotine; Parkinson’s disease
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2012.38

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.