title: Heterozygote carriers for CNVs in PARK2 are at increased risk of Parkinson's disease.
abstract: Together with point mutations, homozygous deletions or duplications in PARK2 are responsible for the majority of autosomal recessive juvenile Parkinsonism. It is debated, however, whether heterozygous carriers of these mutations are at increased risk of Parkinson's disease (PD). Our goal was to determine whether heterozygous carriers of copy number variants (CNVs) affecting exons of the PARK2 gene are at risk of PD that is greater than that of non-carriers. We searched for CNVs affecting exons of PARK2 in a sample of 105 749 genotyped Icelanders. In total, 989 carriers, including 24 diagnosed with PD, were identified. The heterozygous carriers were tested for association in a sample of 1415 PD patients and 40 474 controls ≥65 years of age. PD patients were more often heterozygous carriers of PARK2 CNVs than controls [odds ratio (OR) = 1.69, P = 0.03] and compound heterozygous PD patients for a CNV and a missense mutation were not found. Furthermore, we conducted a meta-analysis of studies reporting on case-control samples screened for heterozygous PARK2 CNVs. Ten studies were included in the final analysis, with 4538 cases and 4213 controls. The pooled OR and P-value for the published and Icelandic results showed significant association between PARK2 CNVs and risk of PD (OR = 2.11, P = 2.54 × 10(-6)). Our analysis shows that heterozygous carriers of CNVs affecting exons of PARK2 have greater risk of PD than non-carriers.
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland, Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen D-72076, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Huttenlocher
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Hafdis T
authors.initials: HT
authors.lastname: Helgadottir
authors.affiliation: Department of Neurology, National University Hospital, Reykjavik 101, Iceland, Department of Neurology, MEHT, Broomfield Hospital, Court Road, Essex CM1 7ET, UK, Neuroscience Department, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK and.
authors.forename: Sigurlaug
authors.initials: S
authors.lastname: Sveinbjörnsdóttir
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen D-72076, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen D-72076, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland, Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland kstefans@decode.is.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007055:Iceland; D010300:Parkinson Disease / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein