Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience
- PMID: 29183403
- PMCID: PMC5706401
- DOI: 10.1186/s13073-017-0486-1
Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience
Erratum in
-
Correction to: Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.Genome Med. 2018 Jan 12;10(1):4. doi: 10.1186/s13073-018-0516-7. Genome Med. 2018. PMID: 29329552 Free PMC article.
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.
Conflict of interest statement
Ethics approval and consent to participate
All research reported in this manuscript complies with the Declaration of Helsinki and was approved by the Brigham Young University Institutional Review Board (approval number E110252) and Utah State University Institutional Review Board (approval number CCSMHA5). Informed consent was obtained from all study participants.
Consent for publication
Not applicable.
Competing interests
ADNI has received some funding from the following companies: Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. Private sector contributions were facilitated by the Foundation for the National Institutes of Health (
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Figures



References
-
- Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8. doi: 10.1038/ng.2802. - DOI - PMC - PubMed
-
- Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43(5):429–35. doi: 10.1038/ng.803. - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- U01AG052411/AG/NIA NIH HHS/United States
- U01 AG024904/AG/NIA NIH HHS/United States
- P50 AG005681/AG/NIA NIH HHS/United States
- S10 OD018522/OD/NIH HHS/United States
- P30 AG028740/AG/NIA NIH HHS/United States
- K01 AG046374/AG/NIA NIH HHS/United States
- R01 AG032990/AG/NIA NIH HHS/United States
- R01 NS080820/NS/NINDS NIH HHS/United States
- R01 AG018712/AG/NIA NIH HHS/United States
- U01 AG052411/AG/NIA NIH HHS/United States
- R01 AG042611/AG/NIA NIH HHS/United States
- U19 AG024904/AG/NIA NIH HHS/United States
- RF1 AG051504/AG/NIA NIH HHS/United States
- RF1 AG054052/AG/NIA NIH HHS/United States
- P50 AG005138/AG/NIA NIH HHS/United States
- U01 AG046139/AG/NIA NIH HHS/United States
- U24 NS072026/NS/NINDS NIH HHS/United States
- R01NS080820/NS/NINDS NIH HHS/United States
- P30 AG019610/AG/NIA NIH HHS/United States
- R25 DA027995/DA/NIDA NIH HHS/United States
- RF1AG054052/AG/NIA NIH HHS/United States
- P30 CA042014/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous