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    Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture

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    Author
    Zhang, Q; Sidorenko, J; Couvy-Duchesne, B; Marioni, RE; Wright, MJ; Goate, AM; Marcora, E; Huang, K-L; Porter, T; Laws, SM; ...
    Date
    2020-09-23
    Source Title
    Nature Communications
    Publisher
    NATURE RESEARCH
    University of Melbourne Author/s
    Masters, Colin; Maruff, Paul; Collins, Steven; Lautenschlager, Nicola; Hill, Andrew; Li, Qiao-Xin; Bush, Ashley; Roberts, Blaine; Rowe, Christopher; Ryan, Timothy; ...
    Affiliation
    Anatomy and Neuroscience
    Florey Department of Neuroscience and Mental Health
    Medicine and Radiology
    Biochemistry and Molecular Biology
    Metadata
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    Document Type
    Journal Article
    Citations
    Zhang, Q., Sidorenko, J., Couvy-Duchesne, B., Marioni, R. E., Wright, M. J., Goate, A. M., Marcora, E., Huang, K. -L., Porter, T., Laws, S. M., Sachdev, P. S., Mather, K. A., Armstrong, N. J., Thalamuthu, A., Brodaty, H., Yengo, L., Yang, J., Wray, N. R., McRae, A. F. & Visscher, P. M. (2020). Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture. NATURE COMMUNICATIONS, 11 (1), https://doi.org/10.1038/s41467-020-18534-1.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251639
    DOI
    10.1038/s41467-020-18534-1
    Abstract
    Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.

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    • Minerva Elements Records [45689]
    • Biochemistry and Molecular Biology - Research Publications [787]
    • Medicine and Radiology - Research Publications [2346]
    • Florey Department of Neuroscience and Mental Health - Research Publications [1052]
    • Anatomy and Neuroscience - Research Publications [621]
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