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

Kari Majamaa,Manuela Tan,Thomas Gasser,Hirotaka Iwaki,Peter Heutink,Johan Marinus,Lynne Krohn,Joseph Jankovic,Karl Heilbron,Huw Morris,Ari Siitonen,John Hardy,Lasse Pihlstrøm,Manu Sharma,Sarah Ahmed,Cornelis Blauwendraat,Alexander Pantelyat,Suzanne Lesage,Eliezer Masliah,Xylena Reed,Claudia Schulte,Luigi Ferrucci,Alexis Brice,Mathias Toft,Kathrin Brockmann,Donald Grosset,Lior Greenbaum,Susan M Resnick ,Francis P Grenn ,Liana S Rosenthal ,Juan C Troncoso ,Jennifer A Ruskey ,Mary B Makarious ,R Ileng Kumaran ,Sonja W Scholz ,Lisa M Shulman ,Sharon Hassin‐Baer ,Ted M Dawson ,Jean‐Christophe Corvol ,Rebekah G Langston ,J Raphael Gibbs ,Paul J Cannon ,Mike A Nalls ,Christopher M Morris ,Marya S Sabir ,Dena G Hernandez ,Zhandong Liu ,Nicholas W Wood ,Olga Pletniková ,Roy N Alcalay ,Jacobus J Van Hilten ,Sara Bandrés‐Ciga ,Pentti J Tienari ,Marilyn Albert ,Ziv Gan‐Or ,Johanna Eerola‐Rautio ,Alastair Noyce ,Argye E Hillis ,Hampton Leonard ,Mark Cookson ,Andrew Singleton

doi:10.1093/brain/awz350

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.

Highlights

Heterozygous functional GBA variants are one of the most common genetic risk factors for Parkinson’s disease (PD) and Lewy body dementia (LBD), found in 3-20% of patients in different populations (Blauwendraat et al 2018b; Gan-Or et al 2015c; Guerreiro et al 2018; Lesage et al 2011; Rivas et al 2018)
Initial data overview In total we included 21,478 PD cases and 24,388 controls from International Parkinson’s Disease Genomics Consortium (IPDGC) datasets; 1,176 PD cases, 13,431 proxy PD cases, and 155,325 population controls from the UK Biobank (UKB) dataset; 103 GBA p.N370S PD cases from the McGill dataset; and 622 LBD cases and 782 controls from the Neurodegenerative Diseases Research Unit (NDRU) dataset (Supplementary Table 2)
For LBD, these numbers are likely to be higher as seen in the NDRU-LBD dataset with ~13% of the LBD cases carrying a GBA variant

Summary

Introduction

Heterozygous functional GBA variants are one of the most common genetic risk factors for Parkinson’s disease (PD) and Lewy body dementia (LBD), found in 3-20% of patients in different populations (Blauwendraat et al 2018b; Gan-Or et al 2015c; Guerreiro et al 2018; Lesage et al 2011; Rivas et al 2018). More common variants include p.E326K, p.T369M, p.N370S and p.L444P, whose frequencies vary with ethnicity and are each found on different haplotypes (Blauwendraat et al 2018b; Leija-Salazar et al 2019). In some ethnicities, such as the Ashkenazi Jewish population, certain GBA variants are found in about 5% of unaffected individuals, and 17-20% of PD patients (Gan-Or et al 2008; Ruskey et al 2019; Sidransky et al 2009). Genotype-phenotype studies have shown that PD patients with GBA variants have an earlier age at onset (AAO), faster disease progression, and higher rates of non-motor symptoms, such as rapid eye movement (REM) sleep behaviour disorder (RBD), autonomic dysfunction, hallucinations and cognitive decline, compared to those with non-GBA associated PD (Gan-Or et al 2018)

Methods

Results

Conclusion