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

• Published in: Movement disorders Vol. 35; no. 7; pp. 1245 - 1248
• Main Authors: Hopfner, Franziska, Mueller, Stefanie H., Szymczak, Silke, Junge, Olaf, Tittmann, Lukas, May, Sandra, Lohmann, Katja, Grallert, Harald, Lieb, Wolfgang, Strauch, Konstantin, Müller‐Nurasyid, Martina, Berger, Klaus, Schormair, Barbara, Winkelmann, Juliane, Mollenhauer, Brit, Trenkwalder, Claudia, Maetzler, Walter, Berg, Daniela, Kasten, Meike, Klein, Christine, Höglinger, Günter U., Gasser, Thomas, Deuschl, Günther, Franke, André, Krawczak, Michael, Dempfle, Astrid, Kuhlenbäumer, Gregor
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2020; Wiley Subscription Services, Inc
• Subjects: ATP13A2; chaperone‐mediated‐autophagy; DNA sequencing; GBA; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glucosylceramidase; Glucosylceramidase - genetics; Humans; LAMP1; Lysosme; Lysosomes; Movement disorders; Mutation; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson's disease; Synuclein; TMEM175; VPS13C; α‐synuclein; Parkinson's disease; LAMP1; VPS13C; GBA; ATP13A2; chaperone-mediated-autophagy; TMEM175; Lysosme; α-synuclein
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.28037

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