Orly Goldstein1, Mali Gana-Weisz1, Danielle Cohen-Avinoam1, Tamara Shiner2, Avner Thaler2, Jesse M Cedarbaum3, Sally John4, Maria Lalioti4, Tanya Gurevich2, Anat Bar-Shira1, Anat Mirelman2, Nir Giladi2, Avi Orr-Urtreger5. 1. The Genomic Research Laboratory for Neurodegeneration, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 2. Laboratory for Early Markers of Neurodegeneration, Center for the study of Movement, Cognition and Mobility, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Israel. 3. Biogen, Inc, Cambridge, MA, USA; Coeruleus Clinical Sciences LLC, Woodbridge, CT, USA. 4. Biogen, Inc, Cambridge, MA, USA. 5. The Genomic Research Laboratory for Neurodegeneration, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Israel. Electronic address: aviorr@tasmc.health.gov.il.
Abstract
BACKGROUND: GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. METHODS: 1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. RESULTS: All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86-12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). CONCLUSIONS: Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.
BACKGROUND:GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PDpatients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. METHODS: 1200 consecutively recruited PDpatients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. RESULTS: All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86-12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). CONCLUSIONS: Compared to previous studies, we demonstrate here a higher frequency of PDpatients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.
Authors: Nurit Omer; Nir Giladi; Tanya Gurevich; Anat Bar-Shira; Mali Gana-Weisz; Tal Glinka; Orly Goldstein; Meir Kestenbaum; Jesse M Cedarbaum; Omar S Mabrouk; Kyle B Fraser; Julia C Shirvan; Avi Orr-Urtreger; Anat Mirelman; Avner Thaler Journal: Mov Disord Date: 2021-09-22 Impact factor: 9.698
Authors: Roberto A Ortega; Cuiling Wang; Deborah Raymond; Nicole Bryant; Clemens R Scherzer; Avner Thaler; Roy N Alcalay; Andrew B West; Anat Mirelman; Yuliya Kuras; Karen S Marder; Nir Giladi; Laurie J Ozelius; Susan B Bressman; Rachel Saunders-Pullman Journal: JAMA Netw Open Date: 2021-04-01