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

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.

Keywords: Alpha-synuclein; Copy number variants; Mosaicism; Parkinson's disease; SNCA.

Fig. 1.

SNCA whole gene duplications identified in the UK Biobank cohort.

Fig. 2.

SNCA whole gene deletions and one (likely) partial SNCA deletion (D) identified in the UK Biobank cohort.

Fig. 3.

Partial validation of genomic events of the genotyping array data using exome sequencing data. A) Duplication of the SNCA gene region (subject #dup3), B) Partial duplication of the long arm of chromosome 4 (subject #comp8), C) Partial duplication of the long arm of chromosome 4 (subject #comp17) Red and blue vertical lines represents the SNCA gene body.