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

Authors
Laurie Robak,Iris Jansen
Jeroen Rooij,André Uitterlinden,Robert Kraaij,Joseph Jankovic,Peter Heutink,Joshua Shulman,Mike Nalls,Vincent Plagnol,Dena Hernandez,Manu Sharma,Una‐Marie Sheerin,Mohamad Saad,Javier Simón-Sánchez,Claudia Schulte,Suzanne Lesage,Sigurlaug Sveinbjörnsdóttir,Sampath Arepalli,Roger Barker,Yoav Ben-,Henk Berendse,Daniela Berg,Kailash Bhatia,Rob Bie,Alessandro Biffi,Bas Bloem,Zoltán Bochdanovits,Michael Bonin,José Brás,Kathrin Brockmann,Janet Brooks,David Burn,Elisa Majounie,Gavin Charlesworth,Codrin Lungu,Honglei Chen,Patrick Chinnery,Sean Chong,Carl Clarke,Mark Cookson,Jonathan Cooper,Jean‐Christophe Corvol,Carl Counsell,Philippe Damier,Jean‐François Dartigues,Panos Deloukas,Günther Deuschl,David Dexter,Karin Dijk,Allissa Dillman,F. Durif,Alexandra Dürr,Sarah Edkins,Jonathan Evans,Thomas Foltynie,Jing Dong,Michelle Gardner,J. Gibbs,Alison Goate,Emma Gray,Rita Guerreiro,Clare Harris,Jacobus Hilten,Albert Hofman,Albert Hollenbeck,Janice Holton,Isabel Wurster,Walter Mätzler,Gavin Hudson,Sarah Hunt,Johanna Huttenlocher,Thomas Illig,Pálmi Jónsson,Jean‐Charles Lambert,Cordelia Langford,Andrew Lees,Peter Lichtner,Patricia Limousin,Grisel Lopez,Delia Lorenz,Alisdair McNeill,Catriona Moorby,Matthew Moore,Huw Morris,Karen Morrison,Valentina Escott‐Price,Ese Mudanohwo,Sean O’Sullivan,Justin Pearson,Joel Perlmutter,Hjörvar Pétursson,Pierre Pollak,Bart Post,Simon Potter,Bernard Ravina,Tamás Révész,Olaf Rieß,Fernando Rivadeneira,Patrizia Rizzu,Mina Ryten,Stephen Sawcer,Anthony Schapira,Hans Scheffer,Karen Shaw,Ira Shoulson,Ellen Sidransky,Colin Smith,Chris Spencer,Hreinn Stefánsson,Francesco Bettella,Joanna Stockton,Amy Strange,Kevin Talbot,Carlie Tanner,Avazeh Tashakkori-Ghanbaria,François Tison,Daniah Trabzuni,Bryan Traynor,Daan Velseboer,Marie Vidailhet,Robert Walker,Bart Warrenburg,Mirdhu Wickremaratchi,Nigel Williams,Caroline Williams‐Gray,Sophie Winder‐Rhodes,Kāri Stefánsson,M. Martinez,Nicholas Wood,John Hardy,Alexis Brice,Thomas Gasser,Andrew Singleton
+132 authors
,Michèle Hu
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Oct 12, 2017
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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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