Lubbe, SJ;
Bustos, B;
Hu, J;
Krainc, D;
Joseph, T;
Hehir, J;
Tan, M;
... for International Parkinson’s Disease Genomics Consortium (IPDGC; + view all
(2021)
Assessing the Relationship Between Monoallelic PRKN Mutations and Parkinson's Risk.
Human Molecular Genetics
10.1093/hmg/ddaa273.
(In press).
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Abstract
Biallelic PRKN (Parkin) mutations cause autosomal recessive Parkinson's (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 risk of PD (P = 0.035), with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk (OR = 1.65, P = 3.69E-07). Carriers were shown to have significantly younger ages at onset compared to 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 to 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.
| Type: | Article |
|---|---|
| Title: | Assessing the Relationship Between Monoallelic PRKN Mutations and Parkinson's Risk |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddaa273 |
| Publisher version: | https://doi.org/10.1093/hmg/ddaa273 |
| Language: | English |
| Additional information: | © The Author(s) 2021. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10119916 |
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