Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain 2017 Dec 01;140(12):3191-3203
Date
11/16/2017Pubmed ID
29140481Pubmed Central ID
PMC5841393DOI
10.1093/brain/awx285Scopus ID
2-s2.0-85038218327 (requires institutional sign-in at Scopus site) 285 CitationsAbstract
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.
Author List
Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R, Jankovic J, International Parkinson’s Disease Genomics Consortium (IPDGC), Heutink P, Shulman JMAuthor
Jing Dong PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acid CeramidaseAdult
Aged
Aged, 80 and over
Case-Control Studies
Cathepsin D
Cohort Studies
Exome
Female
Genetic Predisposition to Disease
Genotype
Glucosylceramidase
Humans
Lysosomal Storage Diseases
Male
Middle Aged
Mutation
Organic Anion Transporters
Parkinson Disease
Sphingomyelin Phosphodiesterase
Symporters
