title: Genomewide association study for onset age in Parkinson disease.
abstract: BACKGROUND
  Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age.
  
  
  METHODS
  Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy.
  
  
  RESULTS
  Meta-analysis across the three studies detected consistent association (p < 1 x 10(-5)) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 x 10(-7)) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 x 10(-6)) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases.
  
  
  CONCLUSIONS
  Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.
authors.affiliation: Boston University School of Medicine, Boston, MA, USA. jlatoure@bu.edu
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dumitriu
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Claudio B
authors.initials: CB
authors.lastname: Mariani
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.forename: Cheryl
authors.initials: C
authors.lastname: Halter
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult