Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia
Authors: Blauwendraat Cornelis , Reed Xylena , Krohn Lynne , Heilbron Karl , Bandres-Ciga Sara , Tan Manuela , Gibbs Raphael , Hernandez Dena G. , Kumaran Ravindran , Langston Rebekah , Ponce Luis Bonet , Alcalay Roy N. , Hassin-Baer Sharon , Greenbaum Lior , Iwaki Hirotaka , Leonard Hampton , Grenn Francis P. , Ruskey Jennifer A. , Sabir Marya , Ahmed Sarah , Makarious Mary B. , Pihlstrøm Lasse , Toft Mathias , van Hilten Jacobus J. , Marinus Johan , Schulte Claudia , Brockmann Kathrin , Sharma Manu , Siitonen Ari , Majamaa Kari , Eerola-Rautio Johanna , Tienari Pentti J. ,   The 23andMe Research Team, Pantelyat Alexander , Hillis-Trupe Argye E. , Dawson Ted M. , Rosenthal Liana S. , Albert Marilyn S. , Resnick Susan M. , Ferrucci Luigi , Morris Christopher M. , Pletnikova Olga , Troncoso Juan , Grosset Donald , Lesage Suzanne , Corvol Jean-Christophe , Brice Alexis , Noyce Alastair J. , Masliah Eliezer , Wood Nick , Hardy John , Shulman Lisa M. , Jankovic Joseph , Shulman Joshua M , Heutink Peter , Gasser Thomas , Cannon Paul , Scholz Sonja W. , Morris Huw , Cookson Mark , Nalls Mike A. , Gan-Or Ziv , Singleton Andrew B. ,   on behalf of the International Parkinson’s Disease Genomics Consortium (IPDGC)
Published: August 2019

Parkinson’s disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, 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 PD and Lewy body dementia (LBD). 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 PD risk variants.

Using multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-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 PD 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 neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions.