Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

A Retraction to this article was published on 17 June 2015

Abstract

Late-onset Alzheimer’s disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these—including APBA2, FYN, RNF219 and SV2A—encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.

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Figure 1: Transcriptomic evidence of a pre-LOAD state in unaffected APOE4 brain tissue.
Figure 2: Differential co-expression correlation analysis of the APOE4- and LOAD-associated transcriptomic states.
Figure 3: RNF219 and SV2A modulate APP proteolytic processing and localization in an APOE4-dependent manner.
Figure 4: SV2A inhibition in human induced neurons modifies APP processing in an APOE4-dependent manner.
Figure 5: An RNF219 polymorphism modifies LOAD age-of-onset and amyloid deposition in human brain.

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Acknowledgements

We thank R. Mayeux, G. Di Paulo, S. Small and A. Rosenthal for comments on the manuscript; D. Holtzman and J. Cirrito for antibody reagents; and S. Bajjalieh and J. Yao for SV2A expression vectors. We are especially grateful to the many laboratories who contributed data sets included in this study. The work was supported by grants from the National Institutes of Health (NIH) (R01AG042317 and RO1NS064433). J.H.L. and R.C. were partially funded by R37 AG015473 and R01 MH084995. Additionally, data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (NIH grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica; Biogen Idec; Bristol-Myers Squibb; Eisai; Elan Pharmaceuticals; Eli Lilly; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics, NV; IXICO; Janssen Alzheimer Immunotherapy Research and Development; Johnson and Johnson Pharmaceutical Research and Development; Medpace; Merck; Meso Scale Diagnostics; NeuroRx Research; Novartis; Pfizer; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514.

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A.A., H.R. and R.F. designed studies, interpreted data and wrote the manuscript. H.R. performed the bioinformatics and genetic analysis. R.F. performed the cell culture and biochemistry experiments. L.Q. participated in the generation of hiNs. R.C. and J.H.L. provided support for the genetic analysis. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at (http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf).

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Correspondence to Asa Abeliovich.

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Rhinn, H., Fujita, R., Qiang, L. et al. Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease. Nature 500, 45–50 (2013). https://doi.org/10.1038/nature12415

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