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

3 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

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Research Area: Medical Genetics

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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",

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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 - http://www.scopus.com/inward/record.url?scp=85082929308&partnerID=8YFLogxK

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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