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Genomewide association study for onset age in Parkinson disease

DOI: 10.1186/1471-2350-10-98

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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.Meta-analysis across the three studies detected consistent association (p < 1 × 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 × 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 × 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.Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.Parkinson disease (PD), the second most common neurodegenerative disorder, is characterized by debilitating symptoms of tremor, rigidity, and bradykinesia, usually occurring late in life. PD incidence increases with age from 1.7/10,000 person-years between ages 50 to 59 to 9.3/10,000 person-years between ages 70 to 79 and has a prevalence of approximately 1.8% among people over the age of 65 [1]. While the average age of onset of PD is approximately 60 years, there is wide variation, with some individuals having onset before age 20 and others not until after age 90 [2,3].Five monogenic forms of PD have been identified and characterized by mode of transmission, onset age and protein affected by mutation. These include α-synuclein (SNCA or PARK1) [4], parkin (PARK2) [5], PTEN-induced pu


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