Reference SVA insertion polymorphisms are associated with Parkinson\u2019s Disease progression and differential gene expression

Abigail L Pfaff,Sulev Koks,John P Quinn,Vivien J Bubb

doi:10.1038/s41531-021-00189-4

Abstract

The development of Parkinson’s disease (PD) involves a complex interaction of genetic and environmental factors. Genome-wide association studies using extensive single nucleotide polymorphism datasets have identified many loci involved in disease. However much of the heritability of Parkinson’s disease is still to be identified and the functional elements associated with the risk to be determined and understood. To investigate the component of PD that may involve complex genetic variants we characterised the hominid specific retrotransposon SINE-VNTR-Alus (SVAs) in the Parkinson’s Progression Markers Initiative cohort utilising whole genome sequencing. We identified 81 reference SVAs polymorphic for their presence/absence, seven of which were associated with the progression of the disease and with differential gene expression in whole blood RNA sequencing data. This study highlights the importance of addressing SVA variants and potentially other types of retrotransposons in PD genetics, furthermore, these SVA elements should be considered as regulatory domains that could play a role in disease progression.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 1% of the population over 60 years of age[1]
We aim to investigate the genetic component of PD further by studying other types of variation and their functional consequences and this study focuses on variation generated by a specific family of retrotransposons
The Parkinson’s Progression Markers Initiative (PPMI) cohort, whose whole genome sequence data were analysed in this study, consisted of 179 healthy controls, 371 PD and 58 subjects classified as SWEDD

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 1% of the population over 60 years of age[1]. Genetic studies have played a key role in highlighting pathways involved in disease pathogenesis that include autophagy, mitophagy, and the innate immune system[3,4]. Monogenic forms of the disease contribute a small percentage to the total incidence of the disease, with the majority of cases classed as sporadic and likely caused by a complex interaction of genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) have been crucial in identifying genetic risk factors of idiopathic disease, a large proportion of the disease heritability has yet to be identified[6,7]. Many of the single nucleotide polymorphisms (SNPs) that are associated with disease development are in non-coding regions of the genome and their functional impact is often unknown. We aim to investigate the genetic component of PD further by studying other types of variation and their functional consequences and this study focuses on variation generated by a specific family of retrotransposons

Objectives

Methods

Results