title: Common variants in PARK loci and related genes and Parkinson's disease.
abstract: Rare mutations in PARK loci genes cause Parkinson's disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. A total of 1,103 PD cases from the upper Midwest, USA, were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species-conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case-control analyses were performed to study association with PD susceptibility, while cases-only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64-0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P-values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility but show limited association of other PARK loci and related genes with PD.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Chung
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Armasu
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Biernacka
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Lesnick
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Ortolaza
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Walter A
authors.initials: WA
authors.lastname: Rocca
authors.forename: Demetrius M
authors.initials: DM
authors.lastname: Maraganore
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D016017:Odds Ratio; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein