Genome-Wide Analysis of Structural Variants in Parkinson Disease

Kimberley J Billingsley; Jinhui Ding; Pilar Alvarez Jerez; Anastasia Illarionova; Kristin Levine; Francis P Grenn; Mary B Makarious; Anni Moore; Daniel Vitale; Xylena Reed; Dena Hernandez; Ali Torkamani; Mina Ryten; John Hardy; UK Brain Expression Consortium (UKBEC); 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 E Talkowski; Bradford Casey; Mark R Cookson; Androo Markham; Mike A Nalls; Medhat Mahmoud; Fritz J Sedlazeck; Cornelis Blauwendraat; J Raphael Gibbs; Andrew B Singleton

doi:10.1002/ana.26608

Genome-Wide Analysis of Structural Variants in Parkinson Disease

Ann Neurol. 2023 May;93(5):1012-1022. doi: 10.1002/ana.26608. Epub 2023 Feb 3.

Authors

Kimberley J Billingsley^{1

2}, Jinhui Ding¹, Pilar Alvarez Jerez^{1

2}, Anastasia Illarionova³, Kristin Levine⁴, Francis P Grenn¹, Mary B Makarious¹, Anni Moore¹, Daniel Vitale^{2

4}, Xylena Reed², Dena Hernandez¹, Ali Torkamani⁵, Mina Ryten^{6

7}, John Hardy^{8

9}; UK Brain Expression Consortium (UKBEC); Ruth Chia¹, Sonja W Scholz^{10

11}, Bryan J Traynor^{11

12

13

14

15}, Clifton L Dalgard^{16

17}, Debra J Ehrlich¹⁸, Toshiko Tanaka¹⁹, Luigi Ferrucci¹⁹, Thomas G Beach²⁰, Geidy E Serrano²⁰, John P Quinn²¹, Vivien J Bubb²¹, Ryan L Collins^{22

23

24}, Xuefang Zhao^{22

23}, Mark Walker^{22

23

25}, Emma Pierce-Hoffman^{22

23

25}, Harrison Brand^{22

23

24}, Michael E Talkowski^{22

23

26}, Bradford Casey²⁷, Mark R Cookson¹, Androo Markham²⁸, Mike A Nalls^{1

2

4}, Medhat Mahmoud²⁹, Fritz J Sedlazeck^{29

30}, Cornelis Blauwendraat^{1

2}, J Raphael Gibbs¹, Andrew B Singleton^{1

2}

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
² Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
³ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁴ Data Tecnica International, Washington, DC, USA.
⁵ The Scripps Research Institute, La Jolla, California, USA.
⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁷ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁸ UK Dementia Research Institute and Department of Neurodegenerative Disease and Reta Lila Weston Institute, UCL Queen Square Institute of Neurology and UCL Movement Disorders Centre, University College London, London, UK.
⁹ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, SAR, China.
¹⁰ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
¹¹ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
¹³ Therapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
¹⁴ National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁵ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁶ Department of Anatomy Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
¹⁷ The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
¹⁸ Parkinson's Disease Clinic, Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
¹⁹ Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
²⁰ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.
²¹ Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
²² Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
²³ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (M.I.T) and Harvard USA Cambridge, Massachusetts, USA.
²⁴ Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
²⁵ Data Sciences Platform, Broad Institute of Massachusetts Institute of Technology (M.I.T) and Harvard USA Cambridge, Massachusetts, USA.
²⁶ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
²⁷ The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.
²⁸ Oxford Nanopore Technologies.
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
³⁰ Department of Computer Science, Rice University, Houston, TX, USA.

Abstract

Objective: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.

Methods: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data.

Results: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4.

Interpretation: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012-1022.

© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Genome, Human
Genome-Wide Association Study*
Genotype
Humans
Parkinson Disease* / genetics
Whole Genome Sequencing

Abstract

Publication types

MeSH terms

Grants and funding