Genetic variants in glutamate-, Aβ−, and tau-related pathways determine polygenic risk for Alzheimer's disease

Lawingco, Ted; Chaudhury, Sultan; Brookes, Keeley J.; Guetta-Baranes, Tamar; Guerreiro, Rita; Bras, Jose; Hardy, John; Francis, Paul; Thomas, Alan; Belbin, Olivia; Morgan, Kevin

Abstract

© 2020 Elsevier Inc. Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the “synaptic PRS” in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%–6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.

Citation

Lawingco, T., Chaudhury, S., Brookes, K. J., Guetta-Baranes, T., Guerreiro, R., Bras, J., Hardy, J., Francis, P., Thomas, A., Belbin, O., & Morgan, K. (2021). Genetic variants in glutamate-, Aβ−, and tau-related pathways determine polygenic risk for Alzheimer's disease. Neurobiology of Aging, 101, 299.e13-299.e21. https://doi.org/10.1016/j.neurobiolaging.2020.11.009

• Journal Article Type: Article
• Acceptance Date: Nov 7, 2020
• Online Publication Date: Nov 12, 2020
• Publication Date: 2021-05
• Deposit Date: Nov 20, 2020
• Publicly Available Date: Nov 13, 2021
• Journal: Neurobiology of Aging
• Print ISSN: 0197-4580
• Electronic ISSN: 1558-1497
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 101
• Pages: 299.e13-299.e21
• DOI: https://doi.org/10.1016/j.neurobiolaging.2020.11.009
• Keywords: Polygenic risk score, Late-onset Alzheimer’s disease, Glutamate signaling, Aβ, Tau1
• Public URL: https://nottingham-repository.worktribe.com/output/5055169
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S0197458020303912