title: The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.
abstract: GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.
authors.affiliation: The Genetic Institute, Tel Aviv Sourasky Medical Center, Weizmann Street, 64239, Tel Aviv, Israel.|The Sackler Faculty of Medicine, Tel-Aviv University, Haim Levanon, 69978, Tel Aviv, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Gan-Or
authors.affiliation: The Genetic Institute, Tel Aviv Sourasky Medical Center, Weizmann Street, 64239, Tel Aviv, Israel.|The Sackler Faculty of Medicine, Tel-Aviv University, Haim Levanon, 69978, Tel Aviv, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Amshalom
authors.affiliation: The Genetic Institute, Tel Aviv Sourasky Medical Center, Weizmann Street, 64239, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Bar-Shira
authors.affiliation: The Genetic Institute, Tel Aviv Sourasky Medical Center, Weizmann Street, 64239, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Gana-Weisz
authors.affiliation: Movement Disorders Unit, Department of Neurology, Parkinson Center, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Mirelman
authors.affiliation: Department of Neurology, Columbia Presbyterian Medical Center, Columbia University, West 168th Street, New York, NY, 10032, USA.
authors.forename: K
authors.initials: K
authors.lastname: Marder
authors.affiliation: Department of Neurology, Beth Israel Medical Center, Union Square East, New York, NY, 10003, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bressman
authors.affiliation: Movement Disorders Unit, Department of Neurology, Parkinson Center, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel.|The Sackler Faculty of Medicine, Tel-Aviv University, Haim Levanon, 69978, Tel Aviv, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Giladi
authors.affiliation: The Genetic Institute, Tel Aviv Sourasky Medical Center, Weizmann Street, 64239, Tel Aviv, Israel. aviorr@tlvmc.gov.il.|The Sackler Faculty of Medicine, Tel-Aviv University, Haim Levanon, 69978, Tel Aviv, Israel. aviorr@tlvmc.gov.il.
authors.forename: A
authors.initials: A
authors.lastname: Orr-Urtreger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D060045:Genes, Modifier / Q000235:genetics*; D055106:Genome-Wide Association Study; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D005962:Glucosylceramidase
keywords: BIN1; GBA; Genetics; Parkinson disease