Abstract
Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson’s disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.
Highlights
Parkinson’s disease (PD) is a multifactorial neurodegenerative disease
If the remaining apparent monoallelic cases had a similar rate of occult biallelic mutations, the true underlying monoallelic carrier rate could be estimated to be lower at 0.9%, and there would be no difference between cases and controls (OR = 1.39; 95% confidence interval (CI): 0.90, 2.16; P = 0.117)
Using age at onset (AAO) data from 5710 (87.1%) cases, we found that NeuroX PD cases with single PRKN mutations have significantly lower AAOs than cases without known mutations [average = 61.4 years; β-coefficient (Coeff) = −5.04; 95% CI: −8.32, −1.71; P = 0.003]
Summary
Parkinson’s disease (PD) is a multifactorial neurodegenerative disease. Common variations within 78 independent loci increase PD risk [1]. It has been suggested that single heterozygous pathogenic AR mutations can increase the risk of PD, and several lines of evidence have been provided for and against mutations (reviewed in Klein et al.) [3]. Biallelic AR mutations in PD genes are rare in PD cases, but single heterozygous mutations in specific AR PD genes are more common and are estimated, depending on the population, to occur in between 0.6 and 3% of unaffected control individuals [4,5,6,7]. We investigate whether single carriers of diseasecausing PRKN mutations are at an increased risk for PD using three large independent case-control cohorts using exome-focused genotype data, whole exome sequencing and resequencing (Reseq) data from the International Parkinson’s Disease Genomics Consortium (IPDGC)
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