Handy, A;
Lord, J;
Green, R;
Xu, J;
Aarsland, D;
Velayudhan, L;
Hye, A;
... AddNeuroMed, and the GERAD1 Consortium; + view all
(2021)
Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease.
Journal of Alzheimer's Disease
10.3233/JAD-210462.
(In press).
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Abstract
BACKGROUND: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. OBJECTIVE: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). METHODS: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. RESULTS: For APOE ɛ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. CONCLUSION: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.
| Type: | Article |
|---|---|
| Title: | Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3233/JAD-210462 |
| Publisher version: | https://doi.org/10.3233/JAD-210462 |
| Language: | English |
| Additional information: | © 2021 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0). |
| Keywords: | Alzheimer’s disease, C-reactive protein, apolipoprotein B-100, apolipoprotein E, blood proteins, insulin-like growth factor binding protein 2, mendelian randomization analysis, polygenic trait, vitamin D-binding protein |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Clinical Epidemiology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10135951 |
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