title: A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2.
abstract: OBJECTIVE
  To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study.
  
  
  METHODS
  We studied 1,686 control subjects (mean age 66.1 ± 13.1 years) and 2,091 patients with PD (mean onset age 58.3 ± 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake.
  
  
  RESULTS
  A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 ± 8.6 heterozygous vs 58.5 ± 11.8 normal).
  
  
  CONCLUSIONS
  This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD.
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, NY 12201-2002, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Kay
authors.forename: C F
authors.initials: CF
authors.lastname: Stevens
authors.forename: T H
authors.initials: TH
authors.lastname: Hamza
authors.forename: J S
authors.initials: JS
authors.lastname: Montimurro
authors.forename: C P
authors.initials: CP
authors.lastname: Zabetian
authors.forename: S A
authors.initials: SA
authors.lastname: Factor
authors.forename: A
authors.initials: A
authors.lastname: Samii
authors.forename: A
authors.initials: A
authors.lastname: Griffith
authors.forename: J W
authors.initials: JW
authors.lastname: Roberts
authors.forename: E S
authors.initials: ES
authors.lastname: Molho
authors.forename: D S
authors.initials: DS
authors.lastname: Higgins
authors.forename: S
authors.initials: S
authors.lastname: Gancher
authors.forename: L
authors.initials: L
authors.lastname: Moses
authors.forename: S
authors.initials: S
authors.lastname: Zareparsi
authors.forename: P
authors.initials: P
authors.lastname: Poorkaj
authors.forename: T
authors.initials: T
authors.lastname: Bird
authors.forename: J
authors.initials: J
authors.lastname: Nutt
authors.forename: G D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: H
authors.initials: H
authors.lastname: Payami
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics*; D012016:Reference Values; D017384:Sequence Deletion / Q000235:genetics*; D018709:Statistics, Nonparametric; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein