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

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

doi:10.1016/j.neurobiolaging.2020.11.009

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

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

^*Corresponding author for this work

Wolfson SPaRC

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Neurobiology of Aging
DOIs	https://doi.org/10.1016/j.neurobiolaging.2020.11.009
Publication status	Accepted/In press - 2020

Keywords

Aβ
Glutamate signaling
Late-onset Alzheimer's disease
Polygenic risk score
Tau1

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10.1016/j.neurobiolaging.2020.11.009

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

abstract = "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.",

keywords = "Aβ, Glutamate signaling, Late-onset Alzheimer's disease, Polygenic risk score, Tau1",

author = "Ted Lawingco and Sultan Chaudhury and Brookes, {Keeley J.} and Tamar Guetta-Baranes and Rita Guerreiro and Jose Bras and John Hardy and Paul Francis and Alan Thomas and Olivia Belbin and Kevin Morgan",

year = "2020",

doi = "10.1016/j.neurobiolaging.2020.11.009",

language = "English",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier B.V.",

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T1 - Genetic variants in glutamate-, Aβ−, and tau-related pathways determine polygenic risk for Alzheimer's disease

AU - Lawingco, Ted

AU - Chaudhury, Sultan

AU - Brookes, Keeley J.

AU - Guetta-Baranes, Tamar

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Hardy, John

AU - Francis, Paul

AU - Thomas, Alan

AU - Belbin, Olivia

AU - Morgan, Kevin

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Aβ

KW - Glutamate signaling

KW - Late-onset Alzheimer's disease

KW - Polygenic risk score

KW - Tau1

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SN - 0197-4580

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Keywords

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