Year: 2009
Type: article
Study design: Observational Study
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. CONCLUSION: Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.
Source: BMC Medical Genetics
Authors: Jeanne C Latourelle, Nathan Pankratz, Alexandra Dumitriu, Jemma B Wilk, Stefano Goldwurm, Gianni Pezzoli, Claudio B Mariani, Anita L DeStefano, Cheryl Halter, James F Gusella, William C Nichols, Richard H Myers, Tatiana Foroud, the PSG -PROGENI and GenePD Investigators, Coordinators and Molecular Genetic Laboratories
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,380
Funders: Michael J. Fox Foundation for Parkinson's Research, Mayo Clinic, Harvard NeuroDiscovery Center, Eli Lilly and Company, School of Medicine, Boston University, Johns Hopkins University, University of Rochester, Fondazione Grigioni per il Morbo di Parkinson, National Institutes of Health, Health Science Center, University of Tennessee, University of California, Irvine, School of Medicine, Indiana University, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
OpenAlex ID: W2167594768