Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease
Laurie Robak,Laurie Robak,Iris E. Jansen,Iris E. Jansen,J. van Rooij,Andre G. Uitterlinden,Robert Kraaij,Joseph Jankovic,Peter Heutink,Joshua M. Shulman,B.R. Bloem,Bart Post,Hans Scheffer,B.P.C. van de Warrenburg +13 more
TLDR
It is suggested that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.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.read more
Citations
More filters
Journal ArticleDOI
Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies
Mike A. Nalls,Cornelis Blauwendraat,Costanza L. Vallerga,Karl Heilbron,Sara Bandres-Ciga,Diana Chang,Manuela Tan,Demis A. Kia,Alastair J. Noyce,Alastair J. Noyce,Angli Xue,Jose Bras,Jose Bras,Emily Young,Rainer von Coelln,Javier Simón-Sánchez,Javier Simón-Sánchez,Claudia Schulte,Claudia Schulte,Manu Sharma,Lynne Krohn,Lynne Krohn,Lasse Pihlstrøm,Ari Siitonen,Ari Siitonen,Hirotaka Iwaki,Hirotaka Iwaki,Leonard H,Faraz Faghri,Faraz Faghri,J. Raphael Gibbs,Dena G. Hernandez,Sonja W. Scholz,Sonja W. Scholz,Juan A. Botía,Juan A. Botía,Maria Martinez,Maria Martinez,Jean-Christophe Corvol,Suzanne Lesage,Joseph Jankovic,Lisa M. Shulman,Margaret Sutherland,Pentti J. Tienari,Kari Majamaa,Kari Majamaa,Mathias Toft,Mathias Toft,Ole A. Andreassen,Ole A. Andreassen,Tushar Bangale,Alexis Brice,Jian Yang,Ziv Gan-Or,Ziv Gan-Or,Thomas Gasser,Thomas Gasser,Peter Heutink,Peter Heutink,Joshua M. Shulman,Nicholas W. Wood,David A. Hinds,John Hardy,Huw R. Morris,Jacob Gratten,Peter M. Visscher,Robert R. Graham,Andrew B. Singleton,Astrid Adarmes-Gómez,Miquel Aguilar,Akbota Aitkulova,Vadim Akhmetzhanov,Roy N. Alcalay,Ignacio Alvarez,Victoria Alvarez,Francisco J. Barrero,Jesús Alberto Bergareche Yarza,Inmaculada Bernal-Bernal,Kimberley Billingsley,Marta Blazquez,Marta Bonilla-Toribio,María Teresa Boungiorno,Kathrin Brockmann,Vivien J. Bubb,Dolores Buiza-Rueda,Ana Cámara,Fátima Carrillo,Mario Carrión-Claro,Debora Cerdan,Viorica Chelban,Jordi Clarimón,Carl E Clarke,Yaroslau Compta,Mark R. Cookson,David Craig,Fabrice Danjou,Monica Diez-Fairen,Oriol Dols-Icardo,Jacinto Duarte,Raquel Duran,Francisco Escamilla-Sevilla,Valentina Escott-Price,Mario Ezquerra,Cici Feliz,Manel Fernández,Rubén Fernández-Santiago,Steven Finkbeiner,Thomas Foltynie,Ciara Garcia,Pedro J. Garcia-Ruiz,Maria Jose Gomez Heredia,Pilar Gómez-Garre,Manuel Menéndez González,Isabel González-Aramburu,Sebastian Guelfi,Rita Guerreiro,John Hardy,Sharon Hassin-Baer,Janet Hoenicka,Peter Holmans,Henry Houlden,Jon Infante,Silvia Jesús,Adriano Jimenez-Escrig,Gulnaz Kaishybayeva,Rauan Kaiyrzhanov,Altynay Karimova,Kerri J. Kinghorn,Sulev Kõks,Jaime Kulisevsky,Miguel A. Labrador-Espinosa,Hampton L. Leonard,Patrick A. Lewis,Jose Lopez-Sendon,Ruth C. Lovering,Steven J. Lubbe,Codrin Lungu,Daniel Macias,Claudia Manzoni,Juan Marín,Johan Marinus,María José Martí,Irene Martínez Torres,Juan Carlos Martínez-Castrillo,Marina Mata,Niccolo E. Mencacci,Carlota Méndez-del-Barrio,Ben Middlehurst,Adolfo Mínguez,Pablo Mir,Kin Y. Mok,Esteban Muñoz,Derek P. Narendra,Oluwadamilola O. Ojo,Njideka U Okubadejo,Ana Gorostidi Pagola,Pau Pastor,Francisco Perez Errazquin,Teresa Periñán-Tocino,Helene Plun-Favreau,John P. Quinn,Lea R'Bibo,Xylena Reed,Elisabet Mondragon Rezola,Mie Rizig,Patrizia Rizzu,Laurie Robak,Antonio Sanchez Rodriguez,Guy A. Rouleau,Javier Ruiz-Martínez,Clara Ruz,Mina Ryten,Dinara Sadykova,Sebastian R Schreglmann,Chingiz Shashkin,María Sierra,Esther Suarez-Sanmartin,Pille Taba,Cesar Tabernero,Manuela X Tan,Juan Pablo Tartari,Cristina Tejera-Parrado,Eduard Tolosa,Daniah Trabzuni,Francesc Valldeoriola,Jacobus J. van Hilten,Kendall Van Keuren-Jensen,Laura Vargas-González,Lydia Vela,Francisco Vives,Nigel Williams,Nazira Zharkinbekova,Zharkyn Zharmukhanov,Elena Zholdybayeva,Alexander Zimprich,Pauli Ylikotila,Stephen G. Reich,Joseph M. Savitt,Michelle Agee,Babak Alipanahi,Adam Auton,Robert K. Bell,Katarzyna Bryc,Sarah L. Elson,Pierre Fontanillas,Nicholas A. Furlotte,Karen E. Huber,Barry W. Hicks,Ethan M. Jewett,Yunxuan Jiang,Aaron Kleinman,Keng-Han Lin,Nadia K. Litterman,Jennifer C. McCreight,Matthew H. McIntyre,Kimberly F. McManus,Joanna L. Mountain,Elizabeth S. Noblin,Carrie A.M. Northover,Steven J. Pitts,G. David Poznik,J. Fah Sathirapongsasuti,Janie F. Shelton,Suyash Shringarpure,Chao Tian,Joyce Y. Tung,Vladimir Vacic,Xin Wang,Catherine H. Wilson,Tim J. Anderson,Steven R. Bentley,John C. Dalrymple-Alford,Javed Fowdar,Glenda M. Halliday,Anjali K. Henders,Ian B. Hickie,Irfahan Kassam,Martin A. Kennedy,John B.J. Kwok,Simon J.G. Lewis,George D. Mellick,Grant W. Montgomery,John F. Pearson,Toni L. Pitcher,Julia Sidorenko,Peter A. Silburn,Leanne Wallace,Naomi R. Wray,Futao Zhang +248 more
TL;DR: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified.
Journal ArticleDOI
Lysosomes as dynamic regulators of cell and organismal homeostasis
TL;DR: The modulation of lysosome function could be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.
Journal ArticleDOI
The genetic architecture of Parkinson's disease
TL;DR: Multiple efforts have been made to investigate the genetic architecture of Parkinson's disease, and emerging technologies, such as machine learning, single-cell RNA sequencing, and high-throughput screens, will improve the understanding of genetic risk.
Journal ArticleDOI
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
TL;DR: If the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned, and lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.
Journal ArticleDOI
Converging pathways in neurodegeneration, from genetics to mechanisms.
TL;DR: The intricate genotype–phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies are reviewed, revealing shared pathogenic mechanisms and emerging therapeutic opportunities and challenges.
References
More filters
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
A Simple Sequentially Rejective Multiple Test Procedure
TL;DR: In this paper, a simple and widely accepted multiple test procedure of the sequentially rejective type is presented, i.e. hypotheses are rejected one at a time until no further rejections can be done.
Journal ArticleDOI
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
Journal ArticleDOI
An integrated map of genetic variation from 1,092 human genomes
Gonçalo R. Abecasis,Adam Auton,Lisa D. Brooks,Mark A. DePristo,Richard Durbin,Robert E. Handsaker,Robert E. Handsaker,Hyun Min Kang,Gabor T. Marth,Gil McVean +9 more
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
Related Papers (5)
Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease
Ellen Sidransky,Mike A. Nalls,Jan O. Aasly,Judith Aharon-Peretz,Grazia Annesi,Egberto Reis Barbosa,Anat Bar-Shira,Daniela Berg,Jose Bras,Jose Bras,Alexis Brice,Alexis Brice,Chiung-Mei Chen,Lorraine N. Clark,Christel Condroyer,Elvira Valeria De Marco,Alexandra Durr,Alexandra Durr,Michael J. Eblan,Stanley Fahn,Matthew J. Farrer,Hon-Chung Fung,Ziv Gan-Or,Thomas Gasser,Ruth Gershoni-Baruch,Ruth Gershoni-Baruch,Nir Giladi,Nir Giladi,Alida Griffith,Tanya Gurevich,Tanya Gurevich,Cristina Januário,Peter Kropp,Anthony E. Lang,Guey Jen Lee-Chen,Suzanne Lesage,Karen Marder,Ignacio F. Mata,Anat Mirelman,Jun Mitsui,Ikuko Mizuta,Giuseppe Nicoletti,Giuseppe Nicoletti,Catarina R. Oliveira,Ruth Ottman,Avi Orr-Urtreger,Lygia da Veiga Pereira,Aldo Quattrone,Aldo Quattrone,Ekaterina Rogaeva,Arndt Rolfs,Hanna Rosenbaum,Roberto Rozenberg,Ali Samii,Ali Samii,Ali Samii,Ted Samaddar,Claudia Schulte,Manu Sharma,Manu Sharma,Andrew B. Singleton,Andrew B. Singleton,Mariana Spitz,Mariana Spitz,Eng-King Tan,Eng-King Tan,Nahid Tayebi,Tatsushi Toda,André R. Troiano,Shoji Tsuji,Matthias Wittstock,Tyra G. Wolfsberg,Yih-Ru Wu,Cyrus P. Zabetian,Yi Zhao,Shira G. Ziegler +75 more
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
Mike A. Nalls,Nathan Pankratz,Christina M. Lill,Chuong B. Do,Dena G. Hernandez,Dena G. Hernandez,Mohamad Saad,Mohamad Saad,Mohamad Saad,Anita L. DeStefano,Anita L. DeStefano,Eleanna Kara,Jose Bras,Manu Sharma,Claudia Schulte,Margaux F. Keller,Sampath Arepalli,Christopher Letson,Connor Edsall,Hreinn Stefansson,Xinmin Liu,Hannah A. Pliner,Joseph H. Lee,Rong Cheng,M. Arfan Ikram,John P. A. Ioannidis,Georgios M. Hadjigeorgiou,Joshua C. Bis,Maria Martinez,Maria Martinez,Joel S. Perlmutter,Alison Goate,Karen Marder,Brian K. Fiske,Margaret Sutherland,Georgia Xiromerisiou,Richard H. Myers,Lorraine N. Clark,Kari Stefansson,John Hardy,Peter Heutink,Honglei Chen,Nicholas W. Wood,Henry Houlden,Haydeh Payami,Alexis Brice,Alexis Brice,William K. Scott,Thomas Gasser,Lars Bertram,Nicholas Eriksson,Tatiana Foroud,Andrew B. Singleton +52 more
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more