PT - JOURNAL ARTICLE AU - Cornelis Blauwendraat AU - Xylena Reed AU - Lynne Krohn AU - Karl Heilbron AU - Sara Bandres-Ciga AU - Manuela Tan AU - Raphael Gibbs AU - Dena G. Hernandez AU - Ravindran Kumaran AU - Rebekah Langston AU - Luis Bonet Ponce AU - Roy N. Alcalay AU - Sharon Hassin-Baer AU - Lior Greenbaum AU - Hirotaka Iwaki AU - Hampton Leonard AU - Francis P. Grenn AU - Jennifer A. Ruskey AU - Marya Sabir AU - Sarah Ahmed AU - Mary B. Makarious AU - Lasse Pihlstrøm AU - Mathias Toft AU - Jacobus J. van Hilten AU - Johan Marinus AU - Claudia Schulte AU - Kathrin Brockmann AU - Manu Sharma AU - Ari Siitonen AU - Kari Majamaa AU - Johanna Eerola-Rautio AU - Pentti J. Tienari AU - The 23andMe Research Team AU - Alexander Pantelyat AU - Argye E. Hillis-Trupe AU - Ted M. Dawson AU - Liana S. Rosenthal AU - Marilyn S. Albert AU - Susan M. Resnick AU - Luigi Ferrucci AU - Christopher M. Morris AU - Olga Pletnikova AU - Juan Troncoso AU - Donald Grosset AU - Suzanne Lesage AU - Jean-Christophe Corvol AU - Alexis Brice AU - Alastair J. Noyce AU - Eliezer Masliah AU - Nick Wood AU - John Hardy AU - Lisa M. Shulman AU - Joseph Jankovic AU - Joshua M Shulman AU - Peter Heutink AU - Thomas Gasser AU - Paul Cannon AU - Sonja W. Scholz AU - Huw Morris AU - Mark Cookson AU - Mike A. Nalls AU - Ziv Gan-Or AU - Andrew B. Singleton AU - on behalf of the International Parkinson’s Disease Genomics Consortium (IPDGC) TI - Genetic modifiers of risk and age at onset in <em>GBA</em> associated Parkinson’s disease and Lewy body dementia AID - 10.1101/738351 DP - 2019 Jan 01 TA - bioRxiv PG - 738351 4099 - http://biorxiv.org/content/early/2019/08/18/738351.short 4100 - http://biorxiv.org/content/early/2019/08/18/738351.full AB - 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 &gt;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.