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

By Cornelis Blauwendraat, Mary B Makarious, Hampton Leonard, Sara Bandres Ciga, Hirotaka Iwaki, Mike A Nalls, Alastair J. Noyce, Andrew B. Singleton

Posted 14 Aug 2020
medRxiv DOI: 10.1101/2020.08.11.20172866

Parkinson 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 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 GWAS are a moderate risk factor for PD. The UK Biobank is a large prospective study including 500,000 individuals and has revolutionized human genetics. Here we assessed the frequency of SNCA variation in this cohort and identified 26 subjects carrying variants of interest including duplications (n=6), deletions (n=6) and large complex likely mosaic events (n=14). 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 thresholds for being considered prodromal cases. Four of the 14 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 Parkinson's disease. 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.

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