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. 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

Affiliations

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

Perry G Ridge et al. Genome Med. .

Erratum in

  • Correction to: Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.
    Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, Murcia JDG, Farnham JM, Damato AR, Allen M, Wang X, Harari O, Fernandez VM, Guerreiro R, Bras J, Hardy J, Munger R, Norton M, Sassi C, Singleton A, Younkin SG, Dickson DW, Golde TE, Price ND, Ertekin-Taner N, Cruchaga C, Goate AM, Corcoran C, Tschanz J, Cannon-Albright LA, Kauwe JSK; Alzheimer’s Disease Neuroimaging Initiative. Ridge PG, et al. 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.

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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 (https://fnih.org/). Donors retain no rights to discoveries and are not included in discussions of results or publication decisions. As such, these contributions do not represent a conflict of interest. The remaining authors declare that they have no competing interests

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Overview of the process followed for analysis of data in this project. TLOD theta LOD, UPDB Utah Population Database, CCS Cache County Study on Memory Health and Aging, AGAG Alzheimer’s Genetics Analysis Group, ADNI Alzheimer’s Disease Neuroimaging Initiative. *Although eight variants passed all filters, two representative variants (one from each pedigree) were chosen based on known biology of the genes they reside in
Fig. 2
Fig. 2
Sar1a subtly affects APP processing in vitro. a Full-length APP levels are not altered by Sar1a expression. Immunoblots of N2A695 cells transiently transfected with vectors expressing GFP, Sar1a, scrambled shRNA, or shRNA specific to Sar1a. Open arrowhead, APP; closed arrowhead, CTF-β and CTF-ɑ. b Sar1a expression does not significantly alter extracellular amyloid-beta levels. Conditioned media from N2A695 cells overexpressing or silencing Sar1a were analyzed by ELISA and resulting values were expressed relative to control. c Sar1a expression does not significantly alter sAPP levels. Quantification of immunoblots of sAPPalpha, sAPPbeta, and sAPPtotal. d Sar1a overexpression alters CTF-β and CTF-ɑ. Quantification of immunoblots of full-length APP, CTF-β, and CTF-ɑ. Graphs represent mean ± SEM from at least three independent experiments. *p value < 0.05
Fig. 3
Fig. 3
Rab10 alters APP processing in vitro. a Full-length APP levels are not altered by Rab10 expression. Immunoblots of N2A695 cells transiently transfected with vectors expressing GFP, Rab10, scrambled shRNA, or shRNA specific to Rab10. Open arrowheads, APP; closed arrowheads, CTF-β and CTF-ɑ. b Rab10 expression alters extracellular amyloid-beta levels. Conditioned media from N2A695 cells overexpressing or silencing Rab10 were analyzed by ELISA and resulting values were expressed relative to control. c Rab10 expression does not significantly alter sAPP levels. Quantification of immunoblots of sAPPalpha, sAPPbeta, and sAPPtotal. d Rab10 overexpression alters CTF-β. Quantification of immunoblots of full-length APP, CTF-β, and CTF-ɑ. Graphs represent mean ± SEM from at least three independent experiments. *p value < 0.05

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