Poster No:
851
Submission Type:
Abstract Submission
Authors:
Hyunwoo Lee1, Junpyo Kim1, Han-na Kim2, Bo-Hyun Kim3, Sangwon Seo1
Institutions:
1Samsung medical center, Seoul, Korea, Republic of, 2Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea, Republic of, 3Samsung Medical Center, Seoul, Seoul
First Author:
Hyunwoo Lee
Samsung medical center
Seoul, Korea, Republic of
Co-Author(s):
Junpyo Kim
Samsung medical center
Seoul, Korea, Republic of
Han-na Kim
Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center
Seoul, Korea, Republic of
Sangwon Seo
Samsung medical center
Seoul, Korea, Republic of
Introduction:
According to the amyloid cascade hypothesis in Alzheimer's disease (AD), the accumulation of amyloid-β (Aβ) is crucial in initiating a chain of subsequent events that includes tau aggregation, neuronal death, and cognitive impairment. While previous studies have shown that abnormalities in amyloid biomarkers precede the changes in tau biomarkers, asserting causality based on temporal relationships alone can be debatable. Mendelian randomization (MR) has been proven to be a powerful approach for clarifying causal relationships using genetic variants as instrumental variables. (IVs). In this study, we performed a two-sample bidirectional MR study to dissect the potential causal association of Aβ and tau, leveraging summary statistics data from genome-wide association studies (GWASs).
Methods:
The two-sample MR study was conducted using GWAS summary statistics regarding amyloid PET and tau PET. For the exposure data set, summary statistics of amyloid PET were generated from 13 cohorts, including 11,816 non-Hispanic whites (NHWs) participants. The tau PET GWAS summary statistics were derived from a meta-analysis combining seven GWAS data sets of 1,449 NHW ancestry individuals. We used the inverse-variance weighted (IVW) method as the primary MR analysis, and MR-Egger regression, weighted median, and mode-based analyses were additionally performed to test the robustness of our study. One-sample MR analysis was also performed to reinforce and verify the experimental results of two-sample MR using autopsy data from the Religious Orders Study/Memory and Aging Project cohort. The exposure and outcome variables for the one-sample MR were neuritic plaque burden and neurofibrillary tangle burden determined by neuropathological examination, respectively.
Results:
In total, 20 SNPs identified in amyloid GWAS that were available in the tau PET GWAS summary dataset were included in our two-sample MR analysis. MR results showed a significant causal association between amyloid and tau (IVW method OR 1.77(1.56-2.01), p =7.28⨉10-19), and MR-Egger regression, weighted median, and mode-based analyses showed consistent results. Neither the heterogeneity test for the IVW method (p=0.32) nor the MR-PRESSO global test for horizontal pleiotropy was statistically significant(p=0.38), indicating no heterogeneity or pleiotropy. MR using tau PET as an exposure and amyloid PET as an outcome showed that the causal association was insignificant (p=0.35). Also, the one-sample MR analysis showed the presence of casual direction from neuritic plaque to neurofibrillary tangle (p < 2⨉10-16), and a weak instrument test identified that PRS is eligible as IV.
Conclusions:
MR is a powerful tool for improving causal inference when GWAS summary statistics data are available for exposure and outcome. While the direction of causation between amyloid and tau has been inferred based on the temporal relationship of the biomarkers, our results strengthen evidence for the presence and the direction of causal association.
Genetics:
Genetic Association Studies 1
Novel Imaging Acquisition Methods:
PET 2
Keywords:
Other - Alzheimer`s disease; amyloid-beta; tau; gwas; Two-sample Mendelian randomization
1|2Indicates the priority used for review
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