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A population scale analysis of rare SNCA variation in the UK Biobank

Blauwendraat, C; Makarious, MB; Leonard, HL; Bandres-Ciga, S; Iwaki, H; Nalls, MA; Noyce, AJ; (2021) A population scale analysis of rare SNCA variation in the UK Biobank. Neurobiology of Disease , 148 , Article 105182. 10.1016/j.nbd.2020.105182. Green open access

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Abstract

Parkinson's disease (PD) is a complex neurodegenerative disease with a variety of genetic and environmental factors contributing to disease. The SNCA gene encodes for the alpha-synuclein protein which plays a central role in PD, where aggregates of this protein are one of the pathological hallmarks of disease. Rare point mutations and copy number gains of the SNCA gene have been shown to cause autosomal dominant PD, and common DNA variants identified using Genome-Wide Association Studies (GWAS) are a moderate risk factor for PD. The UK Biobank is a large-scale population prospective study including ~500,000 individuals that has revolutionized human genetics. Here we assessed the frequency of SNCA variation in this cohort and identified 30 subjects carrying variants of interest including duplications (n = 6), deletions (n = 6) and large complex likely mosaic events (n = 18). No known pathogenic missense variants were identified. None of these subjects were reported to be a PD case, although it is possible that these individuals may develop PD at a later age, and whilst three had known prodromal features, these did not meet defined clinical criteria for being considered ‘prodromal’ cases. Seven of the 18 large complex carriers showed a history of blood based cancer. Overall, we identified copy number variants in the SNCA region in a large population based cohort without reported PD phenotype and symptoms. Putative mosaicism of the SNCA gene was identified, however, it is unclear whether it is associated with PD. These individuals are potential candidates for further investigation by performing SNCA RNA and protein expression studies, as well as promising clinical trial candidates to understand how duplication carriers potentially escape PD.

Type: Article
Title: A population scale analysis of rare SNCA variation in the UK Biobank
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.nbd.2020.105182
Publisher version: https://doi.org/10.1016/j.nbd.2020.105182
Language: English
Additional information: This is an Open Access article published under a Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: SNCA, Parkinson's disease, Copy number variants, Alpha-synuclein, Mosaicism
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
URI: https://discovery.ucl.ac.uk/id/eprint/10115251
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