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Cited by 433Lysosomal Storage Disorders ResearchParkinson's Disease Mechanisms and TreatmentsMetabolism and Genetic Disorders

Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease

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Robak, Laurie A, Jansen, Iris E, van Rooij, Jeroen, Uitterlinden, André G, Kraaij, Robert, Jankovic, Joseph, Heutink, Peter, Shulman, Joshua M +133 more·2017·Brain
DOI 10.1093/brain/awx285PMC PMC5841393
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Abstract

Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

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  • NCL5 encodes the bis(monacylglycero)phosphate (BMP) synthase.

    “In contrast to most of the NCL genes, which appear to disrupt protein homeostasis, NCL5 was very recently identified to encode the bis(monacylglycero)phosphate (BMP) synthase.136”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [136]

    The Discussion table lists CLN5 as a neuronal ceroid lipofuscinosis gene, and Variant selection says no CLN5 variants passed the study’s missingness criterion. Neither passage identifies its protein product or says it synthesizes BMP; searches for BMP synthase and CLN5 function found no such statement in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Robak, L. A., Jansen, I. E., van Rooij, J., Uitterlinden, A. G., Kraaij, R., Jankovic, J., Heutink, P., Shulman, J. M., International Parkinson’s Disease Genomics Consortium (IPDGC), Nalls, M. A., Plagnol, V., Hernandez, D. G., Sharma, M., Sheerin, U.-M., Saad, M., Simón-Sánchez, J., Schulte, C., Lesage, S., Sveinbjörnsdóttir, S., Arepalli, S., Barker, R., Ben-, Y., Berendse, H. W., Berg, D., Bhatia, K., de Bie, R. M. A., Biffi, A., Bloem, B., Bochdanovits, Z., Bonin, M., Bras, J. M., Brockmann, K., Brooks, J., Burn, D. J., Majounie, E., Charlesworth, G., Lungu, C., Chen, H., Chinnery, P. F., Chong, S., Clarke, C. E., Cookson, M. R., Mark Cooper, J., Corvol, J. C., Counsell, C., Damier, P., Dartigues, J.-F., Deloukas, P., Deuschl, G., Dexter, D. T., van Dijk, K. D., Dillman, A., Durif, F., Dürr, A., Edkins, S., Evans, J. R., Foltynie, T., Dong, J., Gardner, M., Raphael Gibbs, J., Goate, A., Gray, E., Guerreiro, R., Harris, C., van Hilten, J. J., Hofman, A., Hollenbeck, A., Holton, J., Hu, M., Huang, X., Wurster, I., Mätzler, W., Hudson, G., Hunt, S. E., Huttenlocher, J., Illig, T., Jónsson, P. V., Lambert, J.-C., Langford, C., Lees, A., Lichtner, P., Limousin, P., Lopez, G., Lorenz, D., Lungu, C., McNeill, A., Moorby, C., Moore, M., Morris, H. R., Morrison, K. E., Escott-Price, V., Mudanohwo, E., O’Sullivan, S. S., Pearson, J., Perlmutter, J. S., Pétursson, H., Pollak, P., Post, B., Potter, S., Ravina, B., Revesz, T., Riess, O., Rivadeneira, F., Rizzu, P., Ryten, M., Sawcer, S., Schapira, A., Scheffer, H., Shaw, K., Shoulson, I., Shulman, J., Sidransky, E., Smith, C., Spencer, C. C. A., Stefánsson, H., Bettella, F., Stockton, J. D., Strange, A., Talbot, K., Tanner, C. M., Tashakkori-Ghanbaria, A., Tison, F., Trabzuni, D., Traynor, B. J., Uitterlinden, A. G., Velseboer, D., Vidailhet, M., Walker, R., van de Warrenburg, B., Wickremaratchi, M., Williams, N., Williams-Gray, C. H., Winder-Rhodes, S., Stefánsson, K., Martinez, M., Wood, N. W., Hardy, J., Heutink, P., Brice, A., Gasser, T., & Singleton, A. B.
Affiliations
  • Baylor College of Medicine (US)
  • German Center for Neurodegenerative Diseases (DE)
  • Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
  • Erasmus MC (NL)
  • Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX USA
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2017-11-13
Volume
140
Issue
12
Pages
3191-3203
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awx285
PMC
PMC5841393
OpenAlex
W2782297377
Cited by
433
References
8
Citations by year
2026: 30 · 2025: 49 · 2024: 46 · 2023: 49 · 2022: 48 · 2021: 57 · 2020: 67 · 2019: 57 · 2018: 28 · 2017: 1
FWCI
30.97
Type
journal article
Language
en
Open access
Locations
  • Brain (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • HAL (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Funders
  • National Institutes of Health (Z01-AG000949-02, Z01-ES101986, R01NS037167, R01CA141668, P50NS071674)
  • National Institute on Aging
  • National Institute of Environmental Health Sciences
  • National Institute of Neurological Disorders and Stroke
  • Wellcome Trust (076113, 085475 and 090355)
  • Department of Defense (W81XWH-09-2-0128)
  • Medical Research Council (G0700943)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
Parkinson's disease, lysosomal storage disease, genetic burden, rare variants, glucocerebrosidase, SMPD1, cathepsin D, SLC17A5, ASAH1, lysosomal function, Gaucher disease
MeSH terms
Adult, Aged, Aged, 80 and over, Cathepsin D, Female, Genotype, Glucosylceramidase, Humans, Male, Middle Aged, Mutation, Parkinson Disease, Sphingomyelin Phosphodiesterase, Cohort Studies, Case-Control Studies, Lysosomal Storage Diseases, Genetic Predisposition to Disease, Organic Anion Transporters, Symporters, Acid Ceramidase, Exome

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