The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease

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• 作者：Z. Gan-Or ; I. Amshalom ; A. Bar-Shira ; M. Gana-Weisz ; A. Mirelman…
• 关键词：BIN1 ; GBA ; Genetics ; Parkinson disease
• 刊名：Journal of Neurology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：262
• 期：11
• 页码：2443-2447
• 全文大小：457 KB
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• 作者单位：Z. Gan-Or (1) (3)
  I. Amshalom (1) (3)
  A. Bar-Shira (1)
  M. Gana-Weisz (1)
  A. Mirelman (2)
  K. Marder (4)
  S. Bressman (5)
  N. Giladi (2) (3)
  A. Orr-Urtreger (1) (3)
  
  1. The Genetic Institute, Tel Aviv Sourasky Medical Center, Weizmann Street, 64239, Tel Aviv, Israel
  3. The Sackler Faculty of Medicine, Tel-Aviv University, Haim Levanon, 69978, Tel Aviv, Israel
  2. Movement Disorders Unit, Department of Neurology, Parkinson Center, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 64239, Tel Aviv, Israel
  4. Department of Neurology, Columbia Presbyterian Medical Center, Columbia University, West 168th Street, New York, NY, 10032, USA
  5. Department of Neurology, Beth Israel Medical Center, Union Square East, New York, NY, 10003, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Neurology
  Neurosciences
  Neuroradiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1459

文摘

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.