Genomewide association study for onset age in Parkinson disease.
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.
Latourelle
Jeanne C
JC
Boston University School of Medicine, Boston, MA, USA. jlatoure@bu.edu
Pankratz
Nathan
N
Dumitriu
Alexandra
A
Wilk
Jemma B
JB
Goldwurm
Stefano
S
Pezzoli
Gianni
G
Mariani
Claudio B
CB
DeStefano
Anita L
AL
Halter
Cheryl
C
Gusella
James F
JF
Nichols
William C
WC
Myers
Richard H
RH
Foroud
Tatiana
T
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