GENETIC ANALYSIS OF ONSET AGE OF PARKINSONS DISEASE

Oregon Health And Science University, Portland OR

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Abstract

DESCRIPTION: The goal is to identify the factors that affect age at onset of PD, so that effective strategies can be devised to delay the onset. The Specific Aim of this study is to test for a genetic influence on onset age of PD. Three candidate loci will be examined: Apolipoprotein E (APOE), the human leukocyte antigen A (HLA-A), and cytochrome P450 (CYP2D6). APOE and HLA-A modulate onset age of Alzheimer disease (AD), and may have a similar effect on onset age of PD. The known function of APOE in neuronal repair, and of HLA-A in immune and inflammatory response, suggest that they may play a general role in neurodegeneration. Identification of genes that predispose to more than one neurodegenerative disorder would help understanding of key mechanisms of neurodegeneration. CYP2D6 is involved in metabolism of environmental toxins, and the mutant B allele is reportedly a risk factor for PD and may be associated with earlier disease onset. The subjects will include 600 unrelated patients with diagnosis of idiopathic PD, and 311 relatives from 66 familial PD kindreds. Every subject and key family member will be evaluated by a neurologist for cognitive and motor function, and followed to death for brain autopsy. A blood sample will be obtained for genotyping (by PCR), DNA banking and establishing immortalized cell lines. Genotype-specific age at onset will be tested using Kaplan-Meier/log-rank method to compare the distributions of onset ages, and student t test to compare the mean onset ages. This study utilizes the resources and the long-standing collaboration between AD and PD centers in Portland and Seattle.