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

Laurie A. Robak, Iris E. Jansen, Jeroen van Rooij, André G. Uitterlinden, Robert Kraaij, Joseph Jankovic, Peter Heutink, Joshua M. Shulman, Mike A. Nalls, Vincent Plagnol, Dena G. Hernandez, Manu Sharma, Una Marie Sheerin, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Roger BarkerYoav Ben, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M.A. de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M. Bras, Kathrin Brockmann, Janet Brooks, David J. Burn, Elisa Majounie, Gavin Charlesworth, Codrin Lungu, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, J. Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean François Dartigues, Panos Deloukas, Günther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R. Evans, Thomas Foltynie, Jing Dong, Michelle Gardner, J. Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Isabel Wurster, Walter Mätzler, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Jean Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Codrin Lungu, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R. Morris, Karen E. Morrison, Valentina Escott-Price, Ese Mudanohwo, Sean S. O’sullivan, Justin Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Joshua Shulman, Ellen Sidransky, Colin Smith, Chris C.A. Spencer, Hreinn Stefánsson, Francesco Bettella, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, François Tison, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Maria Martinez, Nicholas W. Wood, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B. Singleton

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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 languageEnglish (US)
Pages (from-to)3191-3203
Number of pages13
JournalBrain
Volume140
Issue number12
DOIs
StatePublished - Dec 1 2017

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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