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Robak, L.A.* ; Jansen, I.E.* ; van Rooij, J.* ; Uitterlinden, A.G.* ; Kraaij, R.* ; Jankovic, J.* ; Heutink, P.* ; Shulman, J.M.* ; International Parkinson's Disease Genomics Consortium (IPDGC) (Lichtner, P. ; Illig, T.)

Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.

Brain 140, 3191-3203 (2017)
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Mutations in the GBA gene, which cause Gaucher disease, are also risk factors for Parkinson's disease. Leveraging sequencing data from a large cohort of patients and controls, Robak, Jansen et al. discover a significant burden of likely damaging variants among 54 lysosomal storage disorder genes in association with Parkinson's disease risk.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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Parkinson's Disease ; Lysosomal Storage Disorders ; Genetics ; Whole Exome Sequencing; Amyotrophic-lateral-sclerosis; Chaperone-mediated Autophagy; Genome-wide Association; Alpha-synuclein; Glucocerebrosidase Gene; Missing Heritability; Gaucher-disease; Mutation Carriers; P.l302p Mutation; Sequencing Data
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Quellenangaben Band: 140, Heft: 12, Seiten: 3191-3203 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Oxford
Begutachtungsstatus Peer reviewed