Document Type
Journal Article
Publication Title
Nature Communications
Volume
11
Issue
1
PubMed ID
32968074
Publisher
Springer Nature
School
Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences
RAS ID
32211
Funders
Commonwealth Scientific and Industrial Research Organisation
Abstract
© 2020, The Author(s). 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.
DOI
10.1038/s41467-020-18534-1
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Zhang, Q., Sidorenko, J., Couvy-Duchesne, B., Marioni, R. E., Wright, M. J., Goate, A. M., ... & Visscher, P.M. (2020). Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture. Nature Communications, 11(1), article 4799. https://doi.org/10.1038/s41467-020-18534-1