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

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

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.

genetics, lysosomal storage disorders, Parkinson's disease, whole exome sequencing
0006-8950
3191-3203
Robak, Laurie A.
61b586e3-c61f-443b-8bdd-5e26b0ba42f3
Jansen, Iris E.
96cf49a4-f529-4e08-b5fa-49d9d323d9de
Van Rooij, Jeroen
76ee68c9-6304-4565-b289-178c54837ba1
Uitterlinden, André G.
dc200777-839b-47ad-9df6-c6c3e2e0b023
Kraaij, Robert
254d6933-6511-4d10-af96-7f58868238bb
Jankovic, Joseph
084ab164-815e-450b-b049-35137c003201
Heutink, Peter
e9d55ff1-9823-4b0e-90b3-822f506d4994
Shulman, Joshua M.
9095c394-9588-45e3-ac68-7f662b4eaa30
Morrison, Karen
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
International Parkinson's Disease Genomics Consortium (IPDGC)
Robak, Laurie A.
61b586e3-c61f-443b-8bdd-5e26b0ba42f3
Jansen, Iris E.
96cf49a4-f529-4e08-b5fa-49d9d323d9de
Van Rooij, Jeroen
76ee68c9-6304-4565-b289-178c54837ba1
Uitterlinden, André G.
dc200777-839b-47ad-9df6-c6c3e2e0b023
Kraaij, Robert
254d6933-6511-4d10-af96-7f58868238bb
Jankovic, Joseph
084ab164-815e-450b-b049-35137c003201
Heutink, Peter
e9d55ff1-9823-4b0e-90b3-822f506d4994
Shulman, Joshua M.
9095c394-9588-45e3-ac68-7f662b4eaa30
Morrison, Karen
f00890f0-2fde-4dbd-a73b-7422e1b0ede8

International Parkinson's Disease Genomics Consortium (IPDGC) (2017) Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain, 140 (12), 3191-3203. (doi:10.1093/brain/awx285).

Record type: Article

Abstract

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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More information

Accepted/In Press date: 10 September 2017
e-pub ahead of print date: 13 November 2017
Published date: 1 December 2017
Keywords: genetics, lysosomal storage disorders, Parkinson's disease, whole exome sequencing

Identifiers

Local EPrints ID: 417054
URI: http://eprints.soton.ac.uk/id/eprint/417054
ISSN: 0006-8950
PURE UUID: 19943bec-9f6b-40df-aa0d-aca63f7d6b18
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

Catalogue record

Date deposited: 18 Jan 2018 17:30
Last modified: 07 Oct 2020 02:09

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Contributors

Author: Laurie A. Robak
Author: Iris E. Jansen
Author: Jeroen Van Rooij
Author: André G. Uitterlinden
Author: Robert Kraaij
Author: Joseph Jankovic
Author: Peter Heutink
Author: Joshua M. Shulman
Author: Karen Morrison ORCID iD
Corporate Author: International Parkinson's Disease Genomics Consortium (IPDGC)

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