We and others have previously established that there is a 2-3 fold increase in risk of idiopathic Parkinson's disease (PD) in first-degree relatives of probands with PD compared to first-degree relatives of controls. The recent identification of a mutation in the alpha-synuclein gene is the first confirmation of a genetic etiology for PD, although this mutation is associated with young age at onset and most likely will account for a very small proportion of familial PD. PD, like Alzheimer's disease may be genetically heterogeneous and different genetic mechanisms may underlie the familial aggregation. Careful inquiry into whether there are clinical phenotypes that are more often associated with a genetic susceptibility to PD and determination of the most likely mode of inheritance of these phenotypes has important implications for the design of genetic linkage studies. We propose to determine whether genetic influences are greater in families of probands with early-onset PD (<50 years) compared to late-onset PD (>50 years) and tremor-dominant PD compared to postural instability gait disorder (PIGD) PD. We will also test 1) whether the increased risk in first-degree relatives is specific for development of these clinically defined subtypes of PD and 2) whether or not the genetic susceptibility to PD also raises risk for essential tremor. We will conduct two separate case-control studies simultaneously. Study 1 is a family study of 300 PD patients from the multi-ethnic community of Washington Heights-Inwood. The 300 controls for these patients will be drawn from two existing cohorts of community controls. Study 2 is a family study of 200 PD patients with age of onset <50 and 200 PD patients with age of onset >50 who attend the service-based Center for Parkinson's Disease at Columbia University. 400 controls will be recruited by random digit dialing using the same area codes and exchanges as the patients and frequency matching on age, gender, ethnicity and education. All first-degree relatives will be interviewed by telephone and those who screen positive for PD or ET will be examined, as will a random sample of 200 screen-negative relatives. We will also investigate whether or not the cumulative incidence of PD to age 90 is higher in relatives of cases from the service-based sample than in relatives of cases from the community based sample, and if so whether this is due to sensitivity of reporting or whether the service-based sample contains a higher proportion of familial cases because of a higher proportion of cases with clinical characteristics associated with a high familial risk. We will use segregation analysis to determine the most likely mode of inheritance of these clinical phenotypes in order to determine the optimal strategy for a future genetic linkage study.
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