Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Cornelis Blauwendraat; Xylena Reed; Lynne Krohn; Karl Heilbron; Sara Bandres-Ciga; Manuela Tan; J Raphael Gibbs; Dena Hernandez; Ravindran Kumaran; Rebekah Langston; Luis Bonet-Ponce; Roy Alcalay; Sharon Hassin-Baer; Lior Greenbaum; Hirotaka Iwaki; Hampton Leonard; Francis Grenn; Jennifer Ruskey; Marya Sabir; Sarah Ahmed; Mary Makarious; Lasse Pihlstrøm; Mathias Toft; Jacobus van Hilten; Johan Marinus; Claudia Schulte; Kathrin Brockmann; Manu Sharma; Ari Siitonen; Kari Majamaa; Johanna Eerola-Rautio; Pentti Tienari; Alexander Pantelyat; Argye Hillis; Ted Dawson; Liana Rosenthal; Marilyn Albert; Susan Resnick; Luigi Ferrucci; Christopher Morris; Olga Pletnikova; Juan Troncoso; Donald Grosset; Suzanne Lesage; Jean-Christophe Corvol; Alexis Brice; Alastair Noyce; Eliezer Masliah; Nick Wood; John Hardy; Lisa Shulman; Joseph Jankovic; Joshua Shulman; Peter Heutink; Thomas Gasser; Paul Cannon; Sonja Scholz; Huw Morris; Mark Cookson; Mike Nalls; Ziv Gan-Or; Andrew Singleton

doi:10.1093/brain/awz350

Journal Articles Brain - A Journal of Neurology Year : 2020

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

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Cornelis Blauwendraat

Function : Author
PersonId : 1275774
ORCID : 0000-0001-9358-8111

National Institute on Aging [Bethesda, USA]

Xylena Reed

Function : Author

National Institute on Aging [Bethesda, USA]

Lynne Krohn

Function : Author
PersonId : 800396
ORCID : 0000-0001-6554-1666

Montreal Neurological Institute and Hospital

Karl Heilbron

Function : Author

23andMe Inc.

Sara Bandres-Ciga

Function : Author

National Institute on Aging [Bethesda, USA]

ibs.GRANADA Instituto de Investigación Biosanitaria [Granada, Spain]

Manuela Tan

Function : Author
PersonId : 1297249
ORCID : 0000-0001-5835-669X

J Raphael Gibbs

Function : Author

National Institute on Aging [Bethesda, USA]

Dena Hernandez

Function : Author

National Institute on Aging [Bethesda, USA]

Ravindran Kumaran

Function : Author

Rebekah Langston

Function : Author

Luis Bonet-Ponce

Function : Author

Roy Alcalay

Function : Author

Columbia University College of Physicians and Surgeons

Taub Institute for Research on Alzheimer's Disease and the Aging Brain

Sharon Hassin-Baer

Function : Author

Chaim Sheba Medical Center

Sackler Faculty of Medicine

Lior Greenbaum

Function : Author

Sackler Faculty of Medicine

Hirotaka Iwaki

Function : Author
PersonId : 1373186
ORCID : 0000-0002-8982-7885

National Institute on Aging [Bethesda, USA]

Hampton Leonard

Function : Author

National Institute on Aging [Bethesda, USA]

Francis Grenn

Function : Author

Jennifer Ruskey

Function : Author

Montreal Neurological Institute and Hospital

Marya Sabir

Function : Author

National Institute of Neurological Disorders and Stroke [Bethesda]

Sarah Ahmed

Function : Author

National Institute of Neurological Disorders and Stroke [Bethesda]

Mary Makarious

Function : Author

Lasse Pihlstrøm

Function : Author

Mathias Toft

Function : Author

Jacobus van Hilten

Function : Author

Johan Marinus

Function : Author

Claudia Schulte

Function : Author

Kathrin Brockmann

Function : Author

Manu Sharma

Function : Author

Ari Siitonen

Function : Author

Kari Majamaa

Function : Author

Johanna Eerola-Rautio

Function : Author

Pentti Tienari

Function : Author

Alexander Pantelyat

Function : Author

Argye Hillis

Function : Author

Ted Dawson

Function : Author
PersonId : 1383475
ORCID : 0000-0002-6459-0893

Liana Rosenthal

Function : Author

Marilyn Albert

Function : Author

Susan Resnick

Function : Author

Luigi Ferrucci

Function : Author

Christopher Morris

Function : Author

Olga Pletnikova

Function : Author

Juan Troncoso

Function : Author

Donald Grosset

Function : Author

Suzanne Lesage

Function : Author

Institut du Cerveau = Paris Brain Institute

Jean-Christophe Corvol

Function : Author

Institut du Cerveau = Paris Brain Institute

Alexis Brice

Function : Author
PersonId : 1104774
ORCID : 0000-0002-0941-3990
IdRef : 050512935

Institut du Cerveau = Paris Brain Institute

Alastair Noyce

Function : Author

Eliezer Masliah

Function : Author

Nick Wood

Function : Author

John Hardy

Function : Author

Lisa Shulman

Function : Author

Joseph Jankovic

Function : Author

Joshua Shulman

Function : Author

Peter Heutink

Function : Author

Thomas Gasser

Function : Author

Paul Cannon

Function : Author

Sonja Scholz

Function : Author

Huw Morris

Function : Author

Mark Cookson

Function : Author

Mike Nalls

Function : Author

Ziv Gan-Or

Function : Author
PersonId : 791221
ORCID : 0000-0003-0332-234X

Andrew Singleton

Function : Author

Abstract

Abstract Parkinson’s disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson’s disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson’s disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson’s disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson’s disease cases, 13 431 Parkinson’s disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson’s disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson’s disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson’s disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson’s disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

Keywords

CTSB GBA Parkinson’s disease SNCA modifiers

Domains

Human health and pathology

Gestionnaire HAL 5 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04578669

Submitted on : Friday, May 17, 2024-9:51:36 AM

Last modification on : Monday, July 8, 2024-4:11:09 PM

Dates and versions

hal-04578669 , version 1 (17-05-2024)

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HAL Id : hal-04578669 , version 1
DOI : 10.1093/brain/awz350
PUBMED : 31755958
PUBMEDCENTRAL : PMC6935749

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Cornelis Blauwendraat, Xylena Reed, Lynne Krohn, Karl Heilbron, Sara Bandres-Ciga, et al.. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain - A Journal of Neurology , 2020, 143 (1), pp.234-248. ⟨10.1093/brain/awz350⟩. ⟨hal-04578669⟩

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Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

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