Case-Control Study of the Parkin Gene in Early-Onset Parkinson Disease

Abstract

Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls.Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged Յ50 years) and controls participating in a familial aggregation study. Patients and Methods:We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction.Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884AϾG) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions:The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

“…Overall, PINK1 heterozygotes were more frequent among cases than in controls (1.7% vs. 1.0%), with an OR of 1.62 (95%CI 0.88 -2.99) that did not reach statistical significance (p=0.121). We applied the same meta-analysis to published Parkin case-control screenings (Lincoln et al, 2003;Clark et al, 2006;Kay et al, 2007;Klein et al, 2007;Lesage et al, 2007), obtaining frequencies more than doubled in cases than in controls (4.5% vs. 1.8%) and a significant OR of 2.53 (95%CI 1. 40-4.56, p=0.002).…”

“…Diagram of odds ratios (ORs, diamonds) and 95% confidence intervals (CI, vertical bars) calculated for heterozygous rare variants in the PINK1 and Parkin genes from selected mutation screenings of cases and controls (see Methods). In the studies by Clark et al (2006) and Lesage et al (2007), ORs cannot be calculated thus the reported figures represent the frequency of heterozygous patients (CI in brackets). …”

A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

“…[10][11][12][13][14]16,17 However, not all studies found a higher frequency in patients than in controls. 20 Although the sampling of patients varied across studies (early-onset, late-onset, familial PD), the frequency of PARK2 mutations in our patients with PD, when subgrouped to match each study, are generally in line with most prior studies.…”

“…The majority of positive results are heterozygous and difficult for clinicians to interpret because whether having one mutation can cause, increase risk, or accelerate onset of Parkinson disease (PD) is unknown. [9][10][11][12][13][14][15][16][17][18][19][20][21] The second aim of our study was to determine, conclusively, if heterozygous mutations are associated with PD. We designed this study specifically to address this question, and to that end, amassed a large sample size to ensure analytic power, analyzed the coding regions for all types of variations, and importantly, used the same rigorous mutation analysis and validation methods in control subjects as in patients.…”

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Many mutations are homozygous or compound heterozygous, but there also exist cases with one single Parkin mutation [222,225], although it is controversial whether these are disease-causing mutations or merely polymorphisms [226].…”