Large-scale rare variant burden testing in Parkinson's disease

Author:

Makarious Mary B123ORCID,Lake Julie1,Pitz Vanessa4,Ye Fu Allen15,Guidubaldi Joseph L46,Solsberg Caroline Warly78,Bandres-Ciga Sara6,Leonard Hampton L169,Kim Jonggeol Jeffrey410,Billingsley Kimberley J16ORCID,Grenn Francis P1,Jerez Pilar Alvarez16,Alvarado Chelsea X69,Iwaki Hirotaka169,Ta Michael69,Vitale Dan69ORCID,Hernandez Dena1,Torkamani Ali11ORCID,Ryten Mina1213ORCID,Hardy John1415,Scholz Sonja W1617ORCID,Traynor Bryan J117,Dalgard Clifton L18,Ehrlich Debra J19,Tanaka Toshiko20ORCID,Ferrucci Luigi20ORCID,Beach Thomas G21,Serrano Geidy E21ORCID,Real Raquel23ORCID,Morris Huw R23ORCID,Ding Jinhui1,Gibbs J Raphael1,Singleton Andrew B16,Nalls Mike A169,Bhangale Tushar22,Blauwendraat Cornelis146ORCID,

Affiliation:

1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, MD 20814 , USA

2. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK

3. UCL Movement Disorders Centre, University College London , London WC1N 3BG , UK

4. Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, MD 20814 , USA

5. Department of Cell Biology and Neuroscience, Rutgers University , Piscataway, NJ 08854 , USA

6. Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20814 , USA

7. Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA

8. Pharmaceutical Sciences and Pharmacogenomics, University of California San Francisco , San Francisco, CA 94143 , USA

9. Data Tecnica International , Washington, DC 20812 , USA

10. Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London , London EC1M 6BQ , UK

11. Department of Integrative Structural and Computational Biology, Scripps Research Institute , La Jolla, CA 92037 , USA

12. NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London , London WC1N 1EH , UK

13. Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London , London WC1N 1EH , UK

14. 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 WC1N 3BG , UK

15. Institute for Advanced Study, The Hong Kong University of Science and Technology , Hong Kong SAR , China

16. Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke , Bethesda, MD 20814 , USA

17. Department of Neurology, Johns Hopkins University Medical Center , Baltimore, MD 21287 , USA

18. The American Genome Center, Uniformed Services University of the Health Sciences , Bethesda, MD 20814 , USA

19. Parkinson’s Disease Clinic, Office of the Clinical Director, National Institute of Neurological Disorders and Stroke , Bethesda, MD 20814 , USA

20. Translational Gerontology Branch, National Institute on Aging, NIH , Baltimore, MD 21224 , USA

21. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute , Sun City, AZ 85351 , USA

22. Department of Human Genetics, Genentech, Inc. , South San Francisco, CA 94080 , USA

Abstract

Abstract Parkinson’s disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson’s disease. To address this gap, we investigated the rare genetic component of Parkinson’s disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson’s disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson’s disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson’s disease. To date, this is the largest analysis of rare genetic variants in Parkinson’s disease.

Funder

Intramural Research Program

National Institutes of Health

National Institute on Aging

National Institute of Neurological Disorders and Stroke

UK Biobank

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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