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Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Yuanjia Wang; Lorraine N. Clark; Elan D. Louis; Helen Mejia-Santana; Juliette Harris; Lucien J. Cote; Cheryl H. Waters; Howard F. Andrews; Blair Ford; Steven Frucht; Stanley Fahn; Ruth Ottman; Daniel Rabinowitz; Karen Marder

Title:
Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method
Author(s):
Wang, Yuanjia
Clark, Lorraine N.
Louis, Elan D.
Mejia-Santana, Helen
Harris, Juliette
Cote, Lucien J.
Waters, Cheryl H.
Andrews, Howard F.
Ford, Blair
Frucht, Steven
Fahn, Stanley
Ottman, Ruth
Rabinowitz, Daniel
Marder, Karen
Date:
Type:
Articles
Department:
Center for Parkinson's Disease and Other Movement Disorders
Volume:
65
Permanent URL:
Book/Journal Title:
Archives of neurology
Abstract:
Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis.
Subject(s):
Neurosciences
Publisher DOI:
http://dx.doi.org/10.1001/archneur.65.4.467
Item views:
487
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