Neuron：新的阿尔茨海默氏症致病基因被发现
生物谷报道：阿耳茨海默氏症Alzheimer’s disease是老年人中最常见的记忆、思考障碍的疾病，又称老年痴呆症。这种渐行性的神经紊乱疾病大约影响着5百万的美国人，而且据估计，到2050年这个数据将增长到3倍。
刊登在6月7日的Neuron杂志上的一篇文章指出，研究着发现了新的阿尔茨海默氏症的致病基因。该研究是在之前的研究基础上，将患有和未患有阿尔茨海默氏症的人的遗传标记作比较，比较患病人群与未患病人群的基因差异，科学家们识别出了一个共同的关键性基因。该基因可以增加人患阿尔茨海默氏症的风险。研究表明GAB2通过与其他基因协作，包括APOE4，可以改变个体的患病风险。这将对预防和治疗阿尔茨海默氏症相关研究有重要的指导作用。
原始出处:
Neuron, Vol 54, 713-720, 07 June 2007
Report
GAB2 Alleles Modify Alzheimer's Risk in APOE 
4 Carriers
Eric M. Reiman,1,2,3,17,18,
Jennifer A. Webster,1,17,18 Amanda J. Myers,4,5,18 John Hardy,5,6 Travis Dunckley,1,17 Victoria L. Zismann,1,17 Keta D. Joshipura,1,17 John V. Pearson,1,17 Diane Hu-Lince,1,17 Matthew J. Huentelman,1,17 David W. Craig,1,17 Keith D. Coon,1,7,17 Winnie S. Liang,1,17 RiLee H. Herbert,1,17 Thomas Beach,8,17 Kristen C. Rohrer,5 Alice S. Zhao,5 Doris Leung,5 Leslie Bryden,5 Lauren Marlowe,5 Mona Kaleem,5 Diego Mastroeni,8 Andrew Grover,8,17 Christopher B. Heward,9 Rivka Ravid,10 Joseph Rogers,8,17 Michael L. Hutton,11 Stacey Melquist,11 Ron C. Petersen,12 Gene E. Alexander,13,17 Richard J. Caselli,14,17 Walter Kukull,16 Andreas Papassotiropoulos,1,15 and Dietrich A. Stephan1,2,17,
1 Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
2 Banner Alzheimer's Institute, Phoenix, AZ 85006, USA
3 Department of Psychiatry, University of Arizona, Tucson, AZ 85724, USA
4 Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
5 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, 20892, USA
6 Reta Lila Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N, 3BG, England
7 Division of Thoracic Oncology Research, St. Joseph's Hospital, Phoenix, AZ 85013, USA
8 Sun Health Research Institute, Sun City, AZ 85351, USA
9 Kronos Science Laboratory, Phoenix, AZ 85016, USA
10 Netherlands Institute for Neurosciences, Dutch Royal Academy of Arts and Sciences, Meibergdreef 47 AB Amsterdam, The Netherlands
11 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
12 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
13 Department of Psychology, Arizona State University, Tempe, AZ 85281, USA
14 Department of Neurology, Mayo Clinic, Scottsdale, AZ 85259, USA
15 Division of Molecular Psychology and Life Sciences Training Facility, Biozentrum, University of Basel, Switzerland
16 National Alzheimer's Coordinating Center, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195, USA
17 Arizona Alzheimer's Consortium, Phoenix AZ 85006, USA
Corresponding author
Eric M. Reiman
eric.reiman@bannerhealth.com
Corresponding author
Dietrich A. Stephan
dstephan@tgen.org
Summary
The apolipoprotein E (APOE) 4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In 4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10−11) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with APOE 4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE 4 carriers and influences Alzheimer's neuropathology.
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