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Brain. 2017 Dec 1;140(12):3191-3203. doi: 10.1093/brain/awx285.

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

Collaborators (132)

Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Arepalli S, Barker R, Ben- Y, Berendse HW, Berg D, Bhatia K, de Bie RMA, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Majounie E, Charlesworth G, Lungu C, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Mark Cooper J, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Deuschl G, Dexter DT, van Dijk KD, Dillman A, Durif F, Dürr A, Edkins S, Evans JR, Foltynie T, Dong J, Gardner M, Raphael Gibbs J, Goate A, Gray E, Guerreiro R, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Wurster I, Mätzler W, Hudson G, Hunt SE, Huttenlocher J, Illig T, Jónsson PV, Lambert JC, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, Lungu C, McNeill A, Moorby C, Moore M, Morris HR, Morrison KE, Escott-Price V, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Pétursson H, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Shulman J, Sidransky E, Smith C, Spencer CCA, Stefánsson H, Bettella F, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori-Ghanbaria A, Tison F, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, van de Warrenburg B, Wickremaratchi M, Williams N, Williams-Gray CH, Winder-Rhodes S, Stefánsson K, Martinez M, Wood NW, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX USA.
2
Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston TX USA.
3
German Center for Neurodegenerative Diseases (DZNE) and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
4
Department of Clinical Genetics, VU University Medical Center, Amsterdam 1081HZ, The Netherlands.
5
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
6
Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, The Netherlands.
7
Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
8
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
9
Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
10
Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.

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.

KEYWORDS:

Parkinson’s disease; genetics; lysosomal storage disorders; whole exome sequencing

PMID:
29140481
PMCID:
PMC5841393
[Available on 2018-12-01]
DOI:
10.1093/brain/awx285
[Indexed for MEDLINE]

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