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Genome Med. 2017 Nov 29;9(1):100. doi: 10.1186/s13073-017-0486-1.

Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

Author information

1
Department of Biology, Brigham Young University, Provo, UT, 84602, USA.
2
Washington University School of Medicine, St. Louis, MO, 63110, USA.
3
Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.
4
Present address: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
5
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
6
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
7
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
8
Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT, 84322, USA.
9
Department of Family Consumer & Human Development, Utah State University, Logan, UT, 84322, USA.
10
National Institute on Aging, Bethesda, MD, 21224, USA.
11
Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Department of Neuroscience, Gainesville, FL, 32610, USA.
12
Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA, 98109, USA.
13
Departments of Neurology and Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
14
Departments of Neuroscience, Genetics and Genomic Sciences, and Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
15
Department of Mathematics and Statistics, Utah State University, Logan, UT, 84322, USA.
16
Department of Psychology, Utah State University, Logan, UT, 84322, USA.
17
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, 84148, USA.
18
Departments of Biology and Neuroscience, Brigham Young University, Provo, UT, 84602, USA. kauwe@byu.edu.

Abstract

BACKGROUND:

While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.

METHODS:

We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs.

RESULTS:

Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04).

CONCLUSIONS:

Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.

KEYWORDS:

Alzheimer’s disease; Linkage analyses; Protective variants; Utah Population Database; Whole genome sequencing

PMID:
29183403
PMCID:
PMC5706401
DOI:
10.1186/s13073-017-0486-1
[Indexed for MEDLINE]
Free PMC Article

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