| Summary: | Context The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. Objective To identify genetic risk factors for idiopathic PD. Design, Setting, and Participants Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. Main Outcome Measures Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. Results Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. Conclusions Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD. Parkinson disease (PD) is a neurodegenerative disease that affects more than a half-million people in the United States.1 The economic, social, and emotional burden of PD will increase as the population ages. Controversy has surrounded the etiology of PD, with evidence suggesting that both genetic and environmental factors influence disease risk. Familial aggregation of PD has been observed for decades.2 Data from family studies, including a recent large study from Iceland,3 have shown that the sibling recurrence risk ratio ranges from 2 to 10, suggesting that a genetic component to PD exists. However, twin studies4- 6 have produced conflicting results about the genetic contributions, suggesting that little if any genetic contribution exists in the development of PD. Previous efforts to identify genetic risk factors for PD have focused primarily on rare, simple autosomal dominant and recessive forms of the disease. Mutations in the α-synuclein gene, located on chromosome 4q, have been shown to be rare causes of autosomal dominant, early-onset PD.7 Mutations in the parkin gene, located on chromosome 6q, have been reported in families with rare autosomal recessive juvenile parkinsonism and autosomal recessive early-onset PD.8,9 Linkage of several large families with autosomal dominant PD to chromosome 2 has been reported,10 but a disease-causing gene remains to be identified. Collectively, these studies have demonstrated genetic effects only for rare single-gene variants of PD. To examine the broader issue of genetic effects in idiopathic PD, we performed a complete genomic screen for linkage analysis in 174 families with PD containing at least 1 affected relative pair.
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