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Polymorphic reference SVAs are associated with Parkinson's disease progression markers and differential gene expression in the PPMI cohort

Pfaff, A.ORCID: 0000-0002-2231-9800, Bubb, V., Quinn, J. and Kõks, S. (2020) Polymorphic reference SVAs are associated with Parkinson's disease progression markers and differential gene expression in the PPMI cohort. Parkinsonism & Related Disorders, 79 (Supp. 1). e30.

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Objective: The aim of our study was to characterise polymorphic reference SINE-VNTR-Alus (SVA) in whole genome sequencing data from the Parkinson's Progression Markers Initiative (PPMI), a longitudinal Parkinson's disease (PD) cohort with extensive clinical and phenotypic data, to address their potential role in the predisposition to and progression of PD. SVAs are a hominid specific composite retrotransposon that are still actively mobilised in the human genome. SVAs can affect gene expression, mRNA splicing and have been identified as the cause of 12 genetic diseases including X-linked dystonia parkinsonism. There are approximately 2700 SVAs in the reference human genome and a small subset are polymorphic for their presence/absence.

Methods: Reference SVAs were genotyped in whole genome sequencing data from the PPMI cohort using the structural variant caller Delly2. A linear mixed-effects model was used to measure the changes in phenotype scores during follow-up visits related to the presence or absence of SVAs identified. In order to evaluate the effect of SVA genotypes on the gene expression profile, differential whole transcriptome analysis based on whole blood RNA sequencing data from PPMI was performed.

Results: We identified 81 polymorphic reference SVAs in 179 healthy controls and 371 PD cases and using logistic regression did not identify any SVAs associated with disease risk. However, analysis of longitudinal data identified 7 SVAs associated with clinical features and progression markers of PD, including a SVA in the intron of the CASP8 gene whose presence was significantly associated with a lower Movement Disorder Society - Unified Parkinson's Disease Rating Scale PartII (p=0.001) after 36 months follow up. Specific genotypes of the 7 SVAs associated with progression markers were shown to affect gene expression in RNA sequencing data.

Conclusions: This study has identified novel genetic variants that are associated with the progression of PD and differential gene expression.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Elsevier
Copyright: © 2020 Elsevier Ltd.
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