The goal is to avoid Parkinson's disease (PD) either by eliminating the cause or delaying the onset. PD is heterogeneous, with a significant genetic component. The working hypothesis is that some genes such as asynuclein and parkin cause PD, others determine ones' susceptibility to neurotoxins and injury, and a third set modulate disease progression and age at onset. Originally studied in the rare autosomal recessive juvenile PD, recent studies suggest parkin may also be involved in common forms of PD. We propose to study parkin in 609 PD patients, 609 control subjects, 100 newborns, 100 healthy elderly, and the key relatives of patients.
The specific aims are to: (1) Determine the frequency of parkin mutations in PD. The impact of parkin in common PD is unknown. We will divide the patients into two groups, each with 300 subjects. The first group will be sequenced and analyzed for deletions and multiplications, to identify new and known mutations. The second group will be screened for mutations found in the first group. (2) Determine age-specific frequency of parkin mutations in controls. The frequency of parkin variations in the population is unknown. We will divide the controls into two groups, each with 300 subjects. The first group will be sequenced and analyzed for deletions and multiplications, to identify new and known mutations, including those that may be absent in patients (protective). The second group will be screened for mutations found in the first group. To examine allele frequency changes by age, 100 newborns and 100 healthy elderly will be studied. (3) Identify and distinguish disease-associated alleles, protective alleles, age at onset modifiers and neutral polymorphisms. We will analyze the first group of 300 patients and 300 controls, confirm the findings in the second group, and perform family-based tests of linkage disequilibrium to rule out false associations due to population stratification. (4) Study mode of inheritance, penetrance and age at onset of parkin mutations. Genotype-phenotype correlation will be used to determine mode of inheritance and test the hypothesis that parkin mutation dosage can cause anticipation. Understanding the mode of inheritance is essential for studies of disease pathogenesis and for counseling families about the risk.
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