Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease

Franziska Hopfner; Stefanie H. Mueller; Silke Szymczak; Olaf Junge; Lukas Tittmann; Sandra May; Katja Lohmann; Harald Grallert; Wolfgang Lieb; Konstantin Strauch; Martina Müller-Nurasyid; Klaus Berger; Barbara Schormair; Juliane Winkelmann; Brit Mollenhauer; Claudia Trenkwalder; Walter Maetzler; Daniela Berg; Meike Kasten; Christine Klein; Günter U. Höglinger; Thomas Gasser; Günther Deuschl; André Franke; Michael Krawczak; Astrid Dempfle; Gregor Kuhlenbäumer

doi:10.1002/mds.28037

Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease

Franziska Hopfner^*, Stefanie H. Mueller, Silke Szymczak, Olaf Junge, Lukas Tittmann, Sandra May, Katja Lohmann, Harald Grallert, Wolfgang Lieb, Konstantin Strauch, Martina Müller-Nurasyid, Klaus Berger, Barbara Schormair, Juliane Winkelmann, Brit Mollenhauer, Claudia Trenkwalder, Walter Maetzler, Daniela Berg, Meike Kasten, Christine KleinGünter U. Höglinger, Thomas Gasser, Günther Deuschl, André Franke, Michael Krawczak, Astrid Dempfle, Gregor Kuhlenbäumer

^*Corresponding author for this work

48 Citations (Scopus)

Abstract

Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD.

Original language	English
Journal	Movement Disorders
Volume	35
Issue number	7
Pages (from-to)	1245-1248
Number of pages	4
ISSN	0885-3185
DOIs	https://doi.org/10.1002/mds.28037
Publication status	Published - 01.07.2020

Funding

This study was funded by the German Research Foundation (KU 1194/8‐1, DE438/11‐1; KR 1093/9‐1), intramural funding of the Department of Neurology, Kiel University, and the Thiemann Foundation. Funding agencies: Franziska Hopfner received grants from the German Research Council and the Thiemann Foundation. Stefanie H. Müller, Silke Szymczak, Olaf Junge, Lukas Tittmann, Sandra May, Katja Lohmann, Harald Grallert, Wolfgang Lieb, Konstantin Strauch, Martina Müller‐Nurasyid, Klaus Berger, Barbara Schormair, Juliane Winkelmann, Walter Maetzler, Meike Kasten, Christine Klein, André Franke, Michael Krawczak, and Astrid Dempfle report no disclosures. Daniela Berg is a member of the Union Chimique Belge (UCB) advisory board and receives grants from the Michael J. Fox Foundation, Janssen Pharmaceutica N.V., German Parkinson's Disease Association (dPV), Bundesministerium für Wirtschaft und Energie (BMWi), Bundesministerium für Bildung und Forschung (BMBF), Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, European Union, Novartis Pharma GmbH, Lundbeck, and the Damp Foundation. Brit Mollenhauer has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced Research Company. Brit Mollenhauer is member of the executive steering committee of the Parkinson Progression Marker Initiative and principal investigator of the Systemic Synuclein Sampling Study of the Michael J. Fox Foundation for Parkinson's Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), European Union (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, and the Michael J. Fox Foundation for Parkinson's Research. Günter U. Höglinger was supported by the German Federal Ministry of Education and Research (BMBF: 01KU1403A EpiPD), Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy–ID 390857198), German Research Foundation grants (HO2402/6‐2, HO2402/18‐1 MSAomics), the NOMIS Foundation (FTLD project), and the European Union/European Federation of Pharmaceutical Industries and Associations (EFPIA)/Innovative Medicines Initiative, Joint Undertaking (IMPRIND, Inhibiting misfolded protein propagation in neurodegenerative diseases; grant no. 116060). Thomas Gasser serves on the editorial board of the . He holds a patent regarding Kinase Associated with Parkinsonism with Pleiomorphic Pathology (KASPP) Leucine Rich Repeat Kinase 2 () gene, its production and use for the detection and treatment of neurodegenerative diseases. Prof. Gasser has received speaker's honoraria from UCB Pharma, Novartis, Teva, and MedUpdate. He is chairman of the scientific advisory board of the "Joint Programming for Neurodegenerative Diseases" program, funded by the European Commission. He has received grant support from the German Research Foundation, the German Federal Ministry of Education and Research, the European Commission, the Helmholtz Association, and the Michael J. Fox Foundation. Claudia Trenkwalder is supported by the Michael J. Fox Foundation and by European Union Horizon 2010. She receives honoraria or consultation fees from UCB, Gruenenthal, and Orion. Claudia Trenkwalder has received speaker's honoraria from Roche and Britannia. Günther Deuschl has received lecture fees from UCB, Medtronic, and Desitin and has been serving as a consultant for Medtronic, Sapiens, Boston Scientific, and Britannica. He received royalties from Thieme publishers. He receives through his institution funding for his research from the German Research Council, the German Ministery of Education and Health, and Medtronic. Gregor Kuhlenbäumer receives research support from the German Research Council and the Christian‐Albrechts‐University Kiel. The Dortmund Health Study was supported by unrestricted grants to the University of Muenster from the German Migraine and Headache Society and a consortium formed with equal shares by Allmiral, Astra‐Zeneca, Berlin‐Chemie, Boehringer Ingelheim Pharma, Boots Healthcare, GlaxoSmithKline, Janssen Cilag, McNeil Pharmaceuticals, MSD Sharp & Dohme, and Pfizer. The KORA study was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, Kooperative Gesundheitsforschung in der Region Augsburg (KORA) research was supported within the Munich Center of Health Sciences (MC‐Health), Ludwig‐Maximilians‐Universität, as part of LMUinnovativ. No sponsor had access to the data nor participated in the writing of the manuscript. All authors are government employees. Journal of Parkinson's Disease LRRK2

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Hopfner, F., Mueller, S. H., Szymczak, S., Junge, O., Tittmann, L., May, S., Lohmann, K., Grallert, H., Lieb, W., Strauch, K., Müller-Nurasyid, M., Berger, K., Schormair, B., Winkelmann, J., Mollenhauer, B., Trenkwalder, C., Maetzler, W., Berg, D., Kasten, M., ... Kuhlenbäumer, G. (2020). Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease. Movement Disorders, 35(7), 1245-1248. https://doi.org/10.1002/mds.28037

@article{7d8327c9e200499ca6be0a7119606811,

title = "Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease",

abstract = "Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD.",

author = "Franziska Hopfner and Mueller, \{Stefanie H.\} and Silke Szymczak and Olaf Junge and Lukas Tittmann and Sandra May and Katja Lohmann and Harald Grallert and Wolfgang Lieb and Konstantin Strauch and Martina M{\"u}ller-Nurasyid and Klaus Berger and Barbara Schormair and Juliane Winkelmann and Brit Mollenhauer and Claudia Trenkwalder and Walter Maetzler and Daniela Berg and Meike Kasten and Christine Klein and H{\"o}glinger, \{G{\"u}nter U.\} and Thomas Gasser and G{\"u}nther Deuschl and Andr{\'e} Franke and Michael Krawczak and Astrid Dempfle and Gregor Kuhlenb{\"a}umer",

year = "2020",

month = jul,

day = "1",

doi = "10.1002/mds.28037",

language = "English",

volume = "35",

pages = "1245--1248",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley \& Sons Inc.",

number = "7",

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Hopfner, F, Mueller, SH, Szymczak, S, Junge, O, Tittmann, L, May, S, Lohmann, K, Grallert, H, Lieb, W, Strauch, K, Müller-Nurasyid, M, Berger, K, Schormair, B, Winkelmann, J, Mollenhauer, B, Trenkwalder, C, Maetzler, W, Berg, D, Kasten, M , Klein, C, Höglinger, GU, Gasser, T, Deuschl, G, Franke, A, Krawczak, M, Dempfle, A & Kuhlenbäumer, G 2020, 'Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease', Movement Disorders, vol. 35, no. 7, pp. 1245-1248. https://doi.org/10.1002/mds.28037

TY - JOUR

T1 - Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease

AU - Hopfner, Franziska

AU - Mueller, Stefanie H.

AU - Szymczak, Silke

AU - Junge, Olaf

AU - Tittmann, Lukas

AU - May, Sandra

AU - Lohmann, Katja

AU - Grallert, Harald

AU - Lieb, Wolfgang

AU - Strauch, Konstantin

AU - Müller-Nurasyid, Martina

AU - Berger, Klaus

AU - Schormair, Barbara

AU - Winkelmann, Juliane

AU - Mollenhauer, Brit

AU - Trenkwalder, Claudia

AU - Maetzler, Walter

AU - Berg, Daniela

AU - Kasten, Meike

AU - Klein, Christine

AU - Höglinger, Günter U.

AU - Gasser, Thomas

AU - Deuschl, Günther

AU - Franke, André

AU - Krawczak, Michael

AU - Dempfle, Astrid

AU - Kuhlenbäumer, Gregor

PY - 2020/7/1

Y1 - 2020/7/1

N2 - Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD.

AB - Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD.

UR - https://www.scopus.com/pages/publications/85082929308

U2 - 10.1002/mds.28037

DO - 10.1002/mds.28037

M3 - Journal articles

C2 - 32267580

AN - SCOPUS:85082929308

SN - 0885-3185

VL - 35

SP - 1245

EP - 1248

JO - Movement Disorders

JF - Movement Disorders

IS - 7

ER -

Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease

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