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.
| Original language | English |
|---|---|
| Pages (from-to) | 3191-3203 |
| Number of pages | 13 |
| Journal | Brain |
| Volume | 140 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2017 |
Keywords
- Parkinson's disease
- genetics
- lysosomal storage disorders
- whole exome sequencing
Fingerprint
Dive into the research topics of 'Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Brain, Vol. 140, No. 12, 01.12.2017, p. 3191-3203.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease
AU - Robak, Laurie A.
AU - Jansen, Iris E.
AU - Rooij, Jeroen van
AU - Uitterlinden, André G.
AU - Kraaij, Robert
AU - Jankovic, Joseph
AU - Heutink, Peter
AU - Shulman, Joshua M.
AU - Nalls, Mike A.
AU - Plagnol, Vincent
AU - Hernandez, Dena G.
AU - Sharma, Manu
AU - Sheerin, Una Marie
AU - Saad, Mohamad
AU - Simón-Sánchez, Javier
AU - Schulte, Claudia
AU - Lesage, Suzanne
AU - Sveinbjörnsdóttir, Sigurlaug
AU - Arepalli, Sampath
AU - Barker, Roger
AU - Ben, Yoav
AU - Berendse, Henk W.
AU - Berg, Daniela
AU - Bhatia, Kailash
AU - de Bie, Rob M.A.
AU - Biffi, Alessandro
AU - Bloem, Bas
AU - Bochdanovits, Zoltan
AU - Bonin, Michael
AU - Bras, Jose M.
AU - Brockmann, Kathrin
AU - Brooks, Janet
AU - Burn, David J.
AU - Majounie, Elisa
AU - Charlesworth, Gavin
AU - Lungu, Codrin
AU - Chen, Honglei
AU - Chinnery, Patrick F.
AU - Chong, Sean
AU - Clarke, Carl E.
AU - Cookson, Mark R.
AU - Cooper, J. Mark
AU - Corvol, Jean Christophe
AU - Counsell, Carl
AU - Damier, Philippe
AU - Dartigues, Jean François
AU - Deloukas, Panos
AU - Deuschl, Günther
AU - Dexter, David T.
AU - van Dijk, Karin D.
AU - Dillman, Allissa
AU - Durif, Frank
AU - Dürr, Alexandra
AU - Edkins, Sarah
AU - Evans, Jonathan R.
AU - Foltynie, Thomas
AU - Dong, Jing
AU - Gardner, Michelle
AU - Gibbs, J. Raphael
AU - Goate, Alison
AU - Gray, Emma
AU - Guerreiro, Rita
AU - Harris, Clare
AU - van Hilten, Jacobus J.
AU - Hofman, Albert
AU - Hollenbeck, Albert
AU - Holton, Janice
AU - Hu, Michele
AU - Huang, Xuemei
AU - Wurster, Isabel
AU - Mätzler, Walter
AU - Hudson, Gavin
AU - Hunt, Sarah E.
AU - Huttenlocher, Johanna
AU - Illig, Thomas
AU - Jónsson, Pálmi V.
AU - Lambert, Jean Charles
AU - Langford, Cordelia
AU - Lees, Andrew
AU - Lichtner, Peter
AU - Limousin, Patricia
AU - Lopez, Grisel
AU - Lorenz, Delia
AU - Lungu, Codrin
AU - McNeill, Alisdair
AU - Moorby, Catriona
AU - Moore, Matthew
AU - Morris, Huw R.
AU - Morrison, Karen E.
AU - Escott-Price, Valentina
AU - Mudanohwo, Ese
AU - O’sullivan, Sean S.
AU - Pearson, Justin
AU - Perlmutter, Joel S.
AU - Pétursson, Hjörvar
AU - Pollak, Pierre
AU - Post, Bart
AU - Potter, Simon
AU - Ravina, Bernard
AU - Revesz, Tamas
AU - Riess, Olaf
AU - Rivadeneira, Fernando
AU - Rizzu, Patrizia
AU - Ryten, Mina
AU - Sawcer, Stephen
AU - Schapira, Anthony
AU - Scheffer, Hans
AU - Shaw, Karen
AU - Shoulson, Ira
AU - Shulman, Joshua
AU - Sidransky, Ellen
AU - Smith, Colin
AU - Spencer, Chris C.A.
AU - Stefánsson, Hreinn
AU - Bettella, Francesco
AU - Stockton, Joanna D.
AU - Strange, Amy
AU - Talbot, Kevin
AU - Tanner, Carlie M.
AU - Tashakkori-Ghanbaria, Avazeh
AU - Tison, François
AU - Trabzuni, Daniah
AU - Traynor, Bryan J.
AU - Uitterlinden, André G.
AU - Velseboer, Daan
AU - Vidailhet, Marie
AU - Walker, Robert
AU - Warrenburg, Bart van de
AU - Wickremaratchi, Mirdhu
AU - Williams, Nigel
AU - Williams-Gray, Caroline H.
AU - Winder-Rhodes, Sophie
AU - Stefánsson, Kári
AU - Martinez, Maria
AU - Wood, Nicholas W.
AU - Hardy, John
AU - Heutink, Peter
AU - Brice, Alexis
AU - Gasser, Thomas
AU - Singleton, Andrew B.
N1 - Funding Information: L.A.R. received support from the T32 GM07526-37, the Pfizer/ACMG Foundation Clinical Genetics Combined Residency for Translational Genomic Scholars, and the American Academy of Neurology Clinical Research Training Fellowship in Parkinson’s disease. J.M.S. is supported by NIH grants (R21NS089854, R01AG050631, R01AG053960, C06RR029965), Huffington Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. I.E.J. and P.H. receive funding from the Prinses Beatrix Spierfonds. P.H. is supported by the EU joint Program-Neurodegenerative Diseases (JPND):COURAGE-PD, and the Federal Ministry of Education and Research Germany (BMBF):MitoPD. The generation and management of the exome sequencing data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The Exome Sequencing data set was funded by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a Complementation Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl; project number CP2010-41). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including Abbvie, Avid Radiopharmaceuticals, Biogen, Bristol-Myers Squibb, Covance, GE Health Care, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Priamal, Roche, Servier and UCB. The IPDGC was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers Z01-AG000949-02 and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128) and The Michael J Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, P50NS 071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by France-Parkinson Association, the French program ‘Investissements d’avenir’ funding (ANR-10-IAIHU-06) and a grant from Assistance Publique-Hôpitaux de Paris (PHRC, AOR-08010) for the French clinical data. This study was also sponsored by the Landspitali University Hospital Research Fund (grant to S.Sv.); Icelandic Research Council (grant to S.Sv.); and European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson’s disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to H.P. and J.Hu). This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to N.W., J.Ha., and A.Sc.). Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). DNA extraction work that was done in the UK was undertaken at University College London Hospitals, University College London, who received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson’s Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. Publisher Copyright: © 2017 The Author. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - Parkinson's disease
KW - genetics
KW - lysosomal storage disorders
KW - whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85038218327&partnerID=8YFLogxK
U2 - 10.1093/brain/awx285
DO - 10.1093/brain/awx285
M3 - Article
C2 - 29140481
AN - SCOPUS:85038218327
SN - 0006-8950
VL - 140
SP - 3191
EP - 3203
JO - Brain
JF - Brain
IS - 12
ER -