Genome-wide analysis of Structural Variants in Parkinson’s Disease using Short-Read Sequencing data
Year: 2022
Type: preprint
Study design: Observational Study
Abstract: Parkinson’s disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinson’s 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 Parkinson’s 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 Parkinson’s 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 Parkinson’s disease to date, this study highlights the need for large-scale long-read datasets to fully elucidate the role of structural variants in Parkinson’s disease.
Authors: Kimberley J. Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Francis P. Grenn, Mary B. Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Ruth Chia, Sonja W. Scholz, Bryan J. Traynor, Clifton L. Dalgard, Debra J. Ehrlich, Toshiko Tanaka, Luigi Ferrucci, Thomas.G. Beach, Geidy E. Serrano, John P. Quinn, Vivien J. Bubb, Ryan L Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison Brand, Michael Talkowski, Bradford Casey, Mark R Cookson, Androo Markham, Mike Nalls, Medhat Mahmoud, Fritz J Sedlazeck, Cornelis Blauwendraat, J. Raphael Gibbs, Andrew B. Singleton
Institutions: National Institutes of Health, National Institute on Aging, German Center for Neurodegenerative Diseases, Data Tecnica International (United States), Scripps Research Institute, NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, Hong Kong University of Science and Technology, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, Johns Hopkins University, National Institute of Neurological Disorders and Stroke, Johns Hopkins Hospital, National Center for Advancing Translational Sciences, Uniformed Services University of the Health Sciences, Banner Sun Health Research Institute, University of Liverpool, Broad Institute, Harvard University, Massachusetts General Hospital, Massachusetts Institute of Technology, Michael J. Fox Foundation, Oxford Nanopore Technologies (United Kingdom), Baylor College of Medicine, Rice University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, Arizona Department of Health Services, Johns Hopkins University, Alzheimer's Society, UK Dementia Research Institute, Arizona Biomedical Research Commission, National Institutes of Health, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1020749929, G1052080286, G1083877947, G1086909361, G1199795973, G1315589061, G135039954, G1381405788, G1606131442, G1617346752, G178910853, G1826063430, G2131872572, G2161113364, G226565915, G2742075923, G2994373740, G3228411741, G3250808129, G3251040009, G3521153818, G3540482749, G4193400840, G4315210197, G4356472589, G4721042799, G4791902628, G5483069995, Understanding the genes for Parkinson's disease, G6030318873, G6256375845, G6535232462, Arizona Alzheimer's Disease Core Center, G7161884846, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, G7747731141, G7836467104, G7924111682, G8098035348, G8508790466, G9000011571, G9000015010, G9000060582, G9000082987, G9000108620, G9000126746, G9000159448, G9000309942, G961669115
OpenAlex ID: W4293267786