Genes Vs Environment

The Parkinson's-Reversing Breakthrough

Parkinson Disease Therapy

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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

Author

Examination of relatives Relative risk Odds ratio

twin environment is only controlled for approximately the first 20 years of life, confounding the interpretation of the environmental and gene-environmental contributions to the disease. Furthermore, most familial PD demonstrates age-dependent penetrance, making misclassification of phenotype possible without longitudinal follow-up of subjects. Early twin studies reporting concordance of MZ twins (11,12) were not supported in larger nonpopulation-based series (13,14). Subsequently, several population-based twin studies have found no difference in concordance between MZ and DZ twins in Finnish (15), Swedish (16), and American (17) populations. In one of these studies (17), the relative risk of PD in MZ twins was 6.0 for those with age at onset less than 50. However, these findings were based upon four concordant MZ, two concordant DZ, no discordant MZ, and 10 discordant DZ twins. Although these numbers are small, these findings are consistent with the family and linkage studies in which genetic contributions appear to be more common in younger-onset cases.

Another technique to determine the relative importance of genetic and environmental influences in the etiology of PD utilizes detailed knowledge of genealogies to calculate a kinship coefficient. The kinship coefficient is defined as the probability that two alleles at the same locus, drawn at random (one from each person), are identical by descent, providing a measure of the degree of relatedness between two individuals. A large study of an Icelandic genetic database found that subjects with PD were significantly more related to each other than controls from the same population (18) leading to the discovery of the PARK10 locus (19). However, the findings of this study are population-specific and may not translate to other populations. For example, using the same methods, a recent study (20) in an Amish community found that subjects with PD were less related to each other than subjects without the evidence of PD. The authors concluded that adult environmental factors are the likely cause of PD in this community.

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