Complex interactions in Parkinson's disease: a two-phased approach.
The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson's disease (PD). In addition, polymorphisms of these three genes have been shown to be independently associated with PD. In a sample of 298 unrelated PD cases and 185 controls, we applied a two-phased approach of recursive partitioning and logistic regression analyses to explore complex interactions. For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003). Our findings are consistent with the hypothesis that PD is a multigenic disorder of the UPS.
Maraganore
Demetrius M
DM
Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. dmaraganore@mayo.edu
de Andrade
Mariza
M
Lesnick
Timothy G
TG
Farrer
Matthew J
MJ
Bower
James H
JH
Hardy
John A
JA
Rocca
Walter A
WA
D016022:Case-Control Studies; D004262:DNA Restriction Enzymes; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008025:Ligases / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D009069:Movement Disorders / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D051843:Synucleins; D013869:Thiolester Hydrolases / Q000235:genetics*; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D013869:Thiolester Hydrolases; D004262:DNA Restriction Enzymes; D043222:Ubiquitin Thiolesterase; D008025:Ligases