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

Mary B Makarious^{1

2

3}, Julie Lake¹, Vanessa Pitz⁴, Allen Ye Fu^{1

5}, Joseph L Guidubaldi^{4

6}, Caroline Warly Solsberg^{7

8}, Sara Bandres-Ciga⁶, Hampton L Leonard^{1

6

9}, Jonggeol Jeffrey Kim^{4

10}, Kimberley J Billingsley^{1

6}, Francis P Grenn¹, Pilar Alvarez Jerez^{1

6}, Chelsea X Alvarado^{6

9}, Hirotaka Iwaki^{1

6

9}, Michael Ta^{6

9}, Dan Vitale^{6

9}, Dena Hernandez¹, Ali Torkamani¹¹, Mina Ryten^{12

13}, John Hardy^{14

15}; UK Brain Expression Consortium (UKBEC),; Sonja W Scholz^{16

17}, Bryan J Traynor^{1

17}, Clifton L Dalgard¹⁸, Debra J Ehrlich¹⁹, Toshiko Tanaka²⁰, Luigi Ferrucci²⁰, Thomas G Beach²¹, Geidy E Serrano²¹, Raquel Real^{2

3}, Huw R Morris^{2

3}, Jinhui Ding¹, J Raphael Gibbs¹, Andrew B Singleton^{1

6}, Mike A Nalls^{1

6

9}, Tushar Bhangale²², Cornelis Blauwendraat^{1

4

6}

Affiliations

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.

PMID: 37348876
PMCID: PMC10629770
DOI: 10.1093/brain/awad214

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

Mary B Makarious et al. Brain. 2023.

. 2023 Nov 2;146(11):4622-4632.

doi: 10.1093/brain/awad214.

Authors

Affiliations

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.

PMID: 37348876
PMCID: PMC10629770
DOI: 10.1093/brain/awad214

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.

Keywords: GBA1; LRRK2; Parkinson’s disease; burden; genetics; rare variant.

Published by Oxford University Press on behalf of the Guarantors of Brain 2023.

PubMed Disclaimer

Conflict of interest statement

H.L.L., H.I., M.T., D.V. and M.A.N. declare that they are consultants employed by Data Tecnica International, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. H.R.M. is employed by UCL and in the last 24 months he reports paid consultancy from Biogen, Biohaven, Lundbeck; lecture fees/honoraria from Wellcome Trust, Movement Disorders Society. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council and Michael J. Fox Foundation. H.R.M. is also a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). T.B. is employed by Genentech, Inc., a member of the Roche group. C.B. takes final responsibility for the decision to submit the paper for publication.

Figures

**Figure 1**
**Graphical representation of the analysis workflow.** (1) Annotation was performed using Variant Effect Predictor (VEP) and four variant groups were selected: (i) missense variants as defined by SnpEff; (ii) moderate or high impact variants as defined by SnpEff/SnpSift; (iii) high confidence Loss-of-Function (LoF) variants as defined by LOFTEE; and (iv) variants with either a CADD Phred score >20 or high confidence LoF variants as defined by LOFTEE. (2) Burden analysis was performed on each dataset separately at rare (minor allele frequency, MAF < 1%) and ultra-rare (MAF < 0.1%) cut-offs. (3) Meta-analysis Strategy 1 using only Parkinson's disease (PD) cases and controls, otherwise referred to as the ‘case-control’ meta-analysis. (4) Meta-analysis Strategy 2 using PD cases, PD proxy cases (siblings and parent) and controls, otherwise referred to as the ‘case-control-proxies’ meta-analysis. UKB = UK Biobank.

See this image and copyright information in PMC

References

1. Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18:1091–1102. - PMC - PubMed
1. Foo JN, Chew EGY, Chung SJ, et al. Identification of risk loci for Parkinson disease in Asians and comparison of risk between Asians and Europeans: a genome-wide association study. JAMA Neurol. 2020;77:746–754. - PMC - PubMed
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1. Singleton A, Hardy J. A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci. Hum Mol Genet. 2011;20:R158–R162. - PMC - PubMed

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

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

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