Genome-wide analysis of Structural Variants in Parkinson's Disease using Short-Read Sequencing data

Abstract

Parkinsons disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinsons disease is driven by genetics. Despite this, the majority of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focussed solely on the contribution of single nucleotide variants. Structural variants represent a significant source of genetic variation in the human genome. However, because assay of this variability is challenging, structural variants have not been cataloged on a genome-wide scale, and their contribution to the risk of Parkinsons disease remains unknown. In this study, we 1) leveraged the GATK-SV pipeline to detect and genotype structural variants in 7,772 short-read sequencing data and 2) generated a subset of matched whole-genome Oxford Nanopore Technologies long-read sequencing data from the PPMI cohort to allow for comprehensive structural variant confirmation. We detected, genotyped, and tested 3,154 high-confidence common structural variant loci, representing over 412 million nucleotides of non-reference genetic variation. Using the long-read sequencing data, we validated three structural variants that may drive the association signals at known Parkinsons disease risk loci, including a 2kb intronic deletion within the gene LRRN4. Further, we confirm that the majority of structural variants in the human genome cannot be detected using short-read sequencing alone, encompassing on average around 4 million nucleotides of inaccessible sequence per genome. Therefore, although these data provide the most comprehensive survey of the contribution of structural variants to the genetic risk of Parkinsons disease to date, this study highlights the need for large-scale long-read datasets to fully elucidate the role of structural variants in Parkinsons disease.

Competing Interest Statement

D.V. and M.A.N.'s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc . BT currently serves on the Editorial board of EclinicalMedicine, JNNP, NBA, is an Associate Editor for Brain and has a collaborative research agreement with Ionis Pharmaceuticals, Roche and Optimeos. FJS receives research support from Illumina, ONT and PacBio. AM works for ONT.M.E.T. receives research funding and/or reagents from Levo Therapeutics, Microsoft Inc., and Illumina Inc.