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

Laurie A. Robak, Iris E. Jansen, Jeroen van Rooij, André G. Uitterlinden, Robert Kraaij, Joseph Jankovic, Peter Heutink, Joshua M. Shulman, Mike A. Nalls, Vincent Plagnol, Dena G. Hernandez, Manu Sharma, Una Marie Sheerin, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Roger BarkerYoav Ben, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M.A. de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M. Bras, Kathrin Brockmann, Janet Brooks, David J. Burn, Elisa Majounie, Gavin Charlesworth, Codrin Lungu, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, J. Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean François Dartigues, Panos Deloukas, Günther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R. Evans, Thomas Foltynie, Jing Dong, Michelle Gardner, J. Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Isabel Wurster, Walter Mätzler, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Jean Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Codrin Lungu, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R. Morris, Karen E. Morrison, Valentina Escott-Price, Ese Mudanohwo, Sean S. O’sullivan, Justin Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Joshua Shulman, Ellen Sidransky, Colin Smith, Chris C.A. Spencer, Hreinn Stefánsson, Francesco Bettella, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, François Tison, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Maria Martinez, Nicholas W. Wood, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B. Singleton

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3191-3203
Number of pages13
JournalBrain
Volume140
Issue number12
DOIs
StatePublished - Dec 1 2017

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Parkinson Disease
Glucosylceramidase
Genes
Exome
Disease Susceptibility
Gaucher Disease
Alleles
Mutation

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Robak, L. A., Jansen, I. E., Rooij, J. V., Uitterlinden, A. G., Kraaij, R., Jankovic, J., ... Singleton, A. B. (2017). Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain, 140(12), 3191-3203. https://doi.org/10.1093/brain/awx285
Robak, Laurie A. ; Jansen, Iris E. ; Rooij, Jeroen van ; Uitterlinden, André G. ; Kraaij, Robert ; Jankovic, Joseph ; Heutink, Peter ; Shulman, Joshua M. ; Nalls, Mike A. ; Plagnol, Vincent ; Hernandez, Dena G. ; Sharma, Manu ; Sheerin, Una Marie ; Saad, Mohamad ; Simón-Sánchez, Javier ; Schulte, Claudia ; Lesage, Suzanne ; Sveinbjörnsdóttir, Sigurlaug ; Arepalli, Sampath ; Barker, Roger ; Ben, Yoav ; Berendse, Henk W. ; Berg, Daniela ; Bhatia, Kailash ; de Bie, Rob M.A. ; Biffi, Alessandro ; Bloem, Bas ; Bochdanovits, Zoltan ; Bonin, Michael ; Bras, Jose M. ; Brockmann, Kathrin ; Brooks, Janet ; Burn, David J. ; Majounie, Elisa ; Charlesworth, Gavin ; Lungu, Codrin ; Chen, Honglei ; Chinnery, Patrick F. ; Chong, Sean ; Clarke, Carl E. ; Cookson, Mark R. ; Cooper, J. Mark ; Corvol, Jean Christophe ; Counsell, Carl ; Damier, Philippe ; Dartigues, Jean François ; Deloukas, Panos ; Deuschl, Günther ; Dexter, David T. ; van Dijk, Karin D. ; Dillman, Allissa ; Durif, Frank ; Dürr, Alexandra ; Edkins, Sarah ; Evans, Jonathan R. ; Foltynie, Thomas ; Dong, Jing ; Gardner, Michelle ; Gibbs, J. Raphael ; Goate, Alison ; Gray, Emma ; Guerreiro, Rita ; Harris, Clare ; van Hilten, Jacobus J. ; Hofman, Albert ; Hollenbeck, Albert ; Holton, Janice ; Hu, Michele ; Huang, Xuemei ; Wurster, Isabel ; Mätzler, Walter ; Hudson, Gavin ; Hunt, Sarah E. ; Huttenlocher, Johanna ; Illig, Thomas ; Jónsson, Pálmi V. ; Lambert, Jean Charles ; Langford, Cordelia ; Lees, Andrew ; Lichtner, Peter ; Limousin, Patricia ; Lopez, Grisel ; Lorenz, Delia ; Lungu, Codrin ; McNeill, Alisdair ; Moorby, Catriona ; Moore, Matthew ; Morris, Huw R. ; Morrison, Karen E. ; Escott-Price, Valentina ; Mudanohwo, Ese ; O’sullivan, Sean S. ; Pearson, Justin ; Perlmutter, Joel S. ; Pétursson, Hjörvar ; Pollak, Pierre ; Post, Bart ; Potter, Simon ; Ravina, Bernard ; Revesz, Tamas ; Riess, Olaf ; Rivadeneira, Fernando ; Rizzu, Patrizia ; Ryten, Mina ; Sawcer, Stephen ; Schapira, Anthony ; Scheffer, Hans ; Shaw, Karen ; Shoulson, Ira ; Shulman, Joshua ; Sidransky, Ellen ; Smith, Colin ; Spencer, Chris C.A. ; Stefánsson, Hreinn ; Bettella, Francesco ; Stockton, Joanna D. ; Strange, Amy ; Talbot, Kevin ; Tanner, Carlie M. ; Tashakkori-Ghanbaria, Avazeh ; Tison, François ; Trabzuni, Daniah ; Traynor, Bryan J. ; Uitterlinden, André G. ; Velseboer, Daan ; Vidailhet, Marie ; Walker, Robert ; Warrenburg, Bart van de ; Wickremaratchi, Mirdhu ; Williams, Nigel ; Williams-Gray, Caroline H. ; Winder-Rhodes, Sophie ; Stefánsson, Kári ; Martinez, Maria ; Wood, Nicholas W. ; Hardy, John ; Heutink, Peter ; Brice, Alexis ; Gasser, Thomas ; Singleton, Andrew B. / Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. In: Brain. 2017 ; Vol. 140, No. 12. pp. 3191-3203.
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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.",
author = "Robak, {Laurie A.} and Jansen, {Iris E.} and Rooij, {Jeroen van} and Uitterlinden, {Andr{\'e} G.} and Robert Kraaij and Joseph Jankovic and Peter Heutink and Shulman, {Joshua M.} and Nalls, {Mike A.} and Vincent Plagnol and Hernandez, {Dena G.} and Manu Sharma and Sheerin, {Una Marie} and Mohamad Saad and Javier Sim{\'o}n-S{\'a}nchez and Claudia Schulte and Suzanne Lesage and Sigurlaug Sveinbj{\"o}rnsd{\'o}ttir and Sampath Arepalli and Roger Barker and Yoav Ben and Berendse, {Henk W.} and Daniela Berg and Kailash Bhatia and {de Bie}, {Rob M.A.} and Alessandro Biffi and Bas Bloem and Zoltan Bochdanovits and Michael Bonin and Bras, {Jose M.} and Kathrin Brockmann and Janet Brooks and Burn, {David J.} and Elisa Majounie and Gavin Charlesworth and Codrin Lungu and Honglei Chen and Chinnery, {Patrick F.} and Sean Chong and Clarke, {Carl E.} and Cookson, {Mark R.} and Cooper, {J. Mark} and Corvol, {Jean Christophe} and Carl Counsell and Philippe Damier and Dartigues, {Jean Fran{\cc}ois} and Panos Deloukas and G{\"u}nther Deuschl and Dexter, {David T.} and {van Dijk}, {Karin D.} and Allissa Dillman and Frank Durif and Alexandra D{\"u}rr and Sarah Edkins and Evans, {Jonathan R.} and Thomas Foltynie and Jing Dong and Michelle Gardner and Gibbs, {J. Raphael} and Alison Goate and Emma Gray and Rita Guerreiro and Clare Harris and {van Hilten}, {Jacobus J.} and Albert Hofman and Albert Hollenbeck and Janice Holton and Michele Hu and Xuemei Huang and Isabel Wurster and Walter M{\"a}tzler and Gavin Hudson and Hunt, {Sarah E.} and Johanna Huttenlocher and Thomas Illig and J{\'o}nsson, {P{\'a}lmi V.} and Lambert, {Jean Charles} and Cordelia Langford and Andrew Lees and Peter Lichtner and Patricia Limousin and Grisel Lopez and Delia Lorenz and Codrin Lungu and Alisdair McNeill and Catriona Moorby and Matthew Moore and Morris, {Huw R.} and Morrison, {Karen E.} and Valentina Escott-Price and Ese Mudanohwo and O’sullivan, {Sean S.} and Justin Pearson and Perlmutter, {Joel S.} and Hj{\"o}rvar P{\'e}tursson and Pierre Pollak and Bart Post and Simon Potter and Bernard Ravina and Tamas Revesz and Olaf Riess and Fernando Rivadeneira and Patrizia Rizzu and Mina Ryten and Stephen Sawcer and Anthony Schapira and Hans Scheffer and Karen Shaw and Ira Shoulson and Joshua Shulman and Ellen Sidransky and Colin Smith and Spencer, {Chris C.A.} and Hreinn Stef{\'a}nsson and Francesco Bettella and Stockton, {Joanna D.} and Amy Strange and Kevin Talbot and Tanner, {Carlie M.} and Avazeh Tashakkori-Ghanbaria and Fran{\cc}ois Tison and Daniah Trabzuni and Traynor, {Bryan J.} and Uitterlinden, {Andr{\'e} G.} and Daan Velseboer and Marie Vidailhet and Robert Walker and Warrenburg, {Bart van de} and Mirdhu Wickremaratchi and Nigel Williams and Williams-Gray, {Caroline H.} and Sophie Winder-Rhodes and K{\'a}ri Stef{\'a}nsson and Maria Martinez and Wood, {Nicholas W.} and John Hardy and Peter Heutink and Alexis Brice and Thomas Gasser and Singleton, {Andrew B.}",
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Robak, LA, Jansen, IE, Rooij, JV, Uitterlinden, AG, Kraaij, R, Jankovic, J, Heutink, P, Shulman, JM, 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, Cooper, JM, 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, Gibbs, JR, 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, Warrenburg, BVD, 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 2017, 'Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease', Brain, vol. 140, no. 12, pp. 3191-3203. https://doi.org/10.1093/brain/awx285

Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. / Robak, Laurie A.; Jansen, Iris E.; Rooij, Jeroen van; Uitterlinden, André G.; Kraaij, Robert; Jankovic, Joseph; Heutink, Peter; Shulman, Joshua M.; Nalls, Mike A.; Plagnol, Vincent; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una Marie; Saad, Mohamad; Simón-Sánchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Arepalli, Sampath; Barker, Roger; Ben, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M.A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Majounie, Elisa; Charlesworth, Gavin; Lungu, Codrin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Dong, Jing; Gardner, Michelle; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Wurster, Isabel; Mätzler, Walter; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Lambert, Jean Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; Lungu, Codrin; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R.; Morrison, Karen E.; Escott-Price, Valentina; Mudanohwo, Ese; O’sullivan, Sean S.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hjörvar; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Shulman, Joshua; Sidransky, Ellen; Smith, Colin; Spencer, Chris C.A.; Stefánsson, Hreinn; Bettella, Francesco; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; Warrenburg, Bart van de; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefánsson, Kári; Martinez, Maria; Wood, Nicholas W.; Hardy, John; Heutink, Peter; Brice, Alexis; Gasser, Thomas; Singleton, Andrew B.

In: Brain, Vol. 140, No. 12, 01.12.2017, p. 3191-3203.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

AU - Robak, Laurie A.

AU - Jansen, Iris E.

AU - Rooij, Jeroen van

AU - Uitterlinden, André G.

AU - Kraaij, Robert

AU - Jankovic, Joseph

AU - Heutink, Peter

AU - Shulman, Joshua M.

AU - Nalls, Mike A.

AU - Plagnol, Vincent

AU - Hernandez, Dena G.

AU - Sharma, Manu

AU - Sheerin, Una Marie

AU - Saad, Mohamad

AU - Simón-Sánchez, Javier

AU - Schulte, Claudia

AU - Lesage, Suzanne

AU - Sveinbjörnsdóttir, Sigurlaug

AU - Arepalli, Sampath

AU - Barker, Roger

AU - Ben, Yoav

AU - Berendse, Henk W.

AU - Berg, Daniela

AU - Bhatia, Kailash

AU - de Bie, Rob M.A.

AU - Biffi, Alessandro

AU - Bloem, Bas

AU - Bochdanovits, Zoltan

AU - Bonin, Michael

AU - Bras, Jose M.

AU - Brockmann, Kathrin

AU - Brooks, Janet

AU - Burn, David J.

AU - Majounie, Elisa

AU - Charlesworth, Gavin

AU - Lungu, Codrin

AU - Chen, Honglei

AU - Chinnery, Patrick F.

AU - Chong, Sean

AU - Clarke, Carl E.

AU - Cookson, Mark R.

AU - Cooper, J. Mark

AU - Corvol, Jean Christophe

AU - Counsell, Carl

AU - Damier, Philippe

AU - Dartigues, Jean François

AU - Deloukas, Panos

AU - Deuschl, Günther

AU - Dexter, David T.

AU - van Dijk, Karin D.

AU - Dillman, Allissa

AU - Durif, Frank

AU - Dürr, Alexandra

AU - Edkins, Sarah

AU - Evans, Jonathan R.

AU - Foltynie, Thomas

AU - Dong, Jing

AU - Gardner, Michelle

AU - Gibbs, J. Raphael

AU - Goate, Alison

AU - Gray, Emma

AU - Guerreiro, Rita

AU - Harris, Clare

AU - van Hilten, Jacobus J.

AU - Hofman, Albert

AU - Hollenbeck, Albert

AU - Holton, Janice

AU - Hu, Michele

AU - Huang, Xuemei

AU - Wurster, Isabel

AU - Mätzler, Walter

AU - Hudson, Gavin

AU - Hunt, Sarah E.

AU - Huttenlocher, Johanna

AU - Illig, Thomas

AU - Jónsson, Pálmi V.

AU - Lambert, Jean Charles

AU - Langford, Cordelia

AU - Lees, Andrew

AU - Lichtner, Peter

AU - Limousin, Patricia

AU - Lopez, Grisel

AU - Lorenz, Delia

AU - Lungu, Codrin

AU - McNeill, Alisdair

AU - Moorby, Catriona

AU - Moore, Matthew

AU - Morris, Huw R.

AU - Morrison, Karen E.

AU - Escott-Price, Valentina

AU - Mudanohwo, Ese

AU - O’sullivan, Sean S.

AU - Pearson, Justin

AU - Perlmutter, Joel S.

AU - Pétursson, Hjörvar

AU - Pollak, Pierre

AU - Post, Bart

AU - Potter, Simon

AU - Ravina, Bernard

AU - Revesz, Tamas

AU - Riess, Olaf

AU - Rivadeneira, Fernando

AU - Rizzu, Patrizia

AU - Ryten, Mina

AU - Sawcer, Stephen

AU - Schapira, Anthony

AU - Scheffer, Hans

AU - Shaw, Karen

AU - Shoulson, Ira

AU - Shulman, Joshua

AU - Sidransky, Ellen

AU - Smith, Colin

AU - Spencer, Chris C.A.

AU - Stefánsson, Hreinn

AU - Bettella, Francesco

AU - Stockton, Joanna D.

AU - Strange, Amy

AU - Talbot, Kevin

AU - Tanner, Carlie M.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Tison, François

AU - Trabzuni, Daniah

AU - Traynor, Bryan J.

AU - Uitterlinden, André G.

AU - Velseboer, Daan

AU - Vidailhet, Marie

AU - Walker, Robert

AU - Warrenburg, Bart van de

AU - Wickremaratchi, Mirdhu

AU - Williams, Nigel

AU - Williams-Gray, Caroline H.

AU - Winder-Rhodes, Sophie

AU - Stefánsson, Kári

AU - Martinez, Maria

AU - Wood, Nicholas W.

AU - Hardy, John

AU - Heutink, Peter

AU - Brice, Alexis

AU - Gasser, Thomas

AU - Singleton, Andrew B.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038218327&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038218327&partnerID=8YFLogxK

U2 - 10.1093/brain/awx285

DO - 10.1093/brain/awx285

M3 - Article

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AN - SCOPUS:85038218327

VL - 140

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JO - Brain

JF - Brain

SN - 0006-8950

IS - 12

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Robak LA, Jansen IE, Rooij JV, Uitterlinden AG, Kraaij R, Jankovic J et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain. 2017 Dec 1;140(12):3191-3203. https://doi.org/10.1093/brain/awx285