In 1949, Mjones (1) conducted the first systematic study of the genetics of Parkinson's disease (PD) and concluded that the disease was autosomal dominant with 60% penetrance. Subsequent studies have found a substantially lower prevalence of familial PD, beginning an ongoing debate regarding the relative importance of genetic versus environmental factors in the pathogenesis of PD. There are several techniques that have been used to determine the genetic and environmental contributions to the etiology of PD, including family studies, twin studies, and population kinship studies.
Family studies are designed to answer three basic questions: (i) Does the disease cluster in families? (ii) Is the clustering due to genetic, shared environmental, or cultural factors? (iii) How is genetic susceptibility inherited?
Clinic-based studies have found that approximately 20% of patients with PD have a positive family history, suggesting that environmental factors play a primary role in the majority of cases (2). Clusters of PD are rare but were described for decades before molecular biology techniques enabling gene isolation were developed (3,4). However, the majority of patients with PD who have a family history are not a member of a large, multi-incident pedigree. Reports of relative risk (RR) rates for first degree relatives of a PD patient vary from 2.3 to 14.6 depending upon methodology (5,6). Studies involving direct examination of all patients and controls typically found a lower genetic risk (Table 1). One family study (7) compared the relative risk of first-degree relatives of early- and late-onset cases to controls, and found a relative risk for siblings of early-onset patients of 7.9 with no increased risk in parents. However, in late-onset families, siblings (RR 3.6) and parents (RR 2.5) had an increased risk of PD compared to controls. Therefore, the heritability of PD, the proportion of variation directly attributable to genetic differences among individuals relative to the total variation in the population, is relatively low in older patients. These findings, in addition to the predominance of young-onset disease in the known genetic parkinsonisms (8-10), suggest that the younger-onset patients may have a different etiology.
Twin studies can provide evidence for genetic or environmental contributions by comparing the concordance of monozygotic (MZ) twins with that of dizygotic (DZ) twins. Since twins typically share the same early environment and monozygotic twins are genetically identical, significantly higher concordance in MZ versus DZ twins implies a genetic basis of the disease. On the other hand, similar concordance in disease rate between MZ and DZ twins implicates early-life, environmental exposures in the etiology of a disease. Appropriately designed twin studies can provide powerful evidence for the genetic or environmental contributions to the disease; however, large sample sizes may be difficult to obtain, and the
TABLE 1 Relative Risk of Parkinson's Disease
Examination of relatives Relative risk Odds ratio
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