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

Authors:
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
Year of publication:
2020
Volume:
35
Issue:
7
Issn:
0885-3185
Journal title abbreviated:
MOVEMENT DISORD
Journal title long:
Movement disorders : official journal of the Movement Disorder Society
Impact factor:
8.679
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. © 2020 International Parkinson and Movement Disorder Society.