title: Complex interactions in Parkinson's disease: a two-phased approach.
abstract: 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.
authors.affiliation: Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. dmaraganore@mayo.edu
authors.forename: Demetrius M
authors.initials: DM
authors.lastname: Maraganore
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Lesnick
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: James H
authors.initials: JH
authors.lastname: Bower
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.forename: Walter A
authors.initials: WA
authors.lastname: Rocca
mesh_terms: 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
chemical_list: 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