Deciphering the causal relationship between blood metabolites and Alzheimers Disease: a Mendelian Randomization study
Bradley Scott Jermy,
Posted 30 Apr 2020
medRxiv DOI: 10.1101/2020.04.28.20083253
Posted 30 Apr 2020
There are currently no disease modifying treatments for Alzheimers Disease (AD). Epidemiological studies have highlighted blood metabolites as potential biomarkers, but possible confounding and reverse causation prevent causal conclusions. Here, we investigated whether nineteen metabolites previously associated with midlife cognitive function, are on the causal pathway to AD. Summary statistics from the largest Genome-Wide Association Studies (GWAS) for AD and for metabolites were used to perform bi-directional univariable Mendelian Randomisation (MR). Bayesian model averaging MR (MR-BMA) was additionally performed to address high correlation between metabolites and to identify metabolite combinations which may be on the AD causal pathway. Univariable MR indicated three Extra-Large High-Density Lipoproteins (XL.HDL) to be on the causal pathway to AD: Free Cholesterol (XL.HDL.FC: OR=0.86, 95% CI=0.78-0.94), Total Lipids (XL.HDL.L: OR=0.88, 95% CI=0.80-0.97), and Phospholipids (XL.HDL.PL: OR=0.87, 95% CI=0.81-0.97); significant at an adjusted threshold of p<0.009. MR-BMA corroborated XL.HDL.FC to be amongst the top three causal metabolites, additionally to Total Cholesterol in XL.HDL (XL.HDL.C) and Glycoprotein Acetyls (GP) (posterior probabilities=0.112, 0.113, 0.287 respectively). Both XL.HDL.C and GP also demonstrated suggestive evidence of univariable causal associations (XL.HDL.C:OR=0.88, 95% CI=0.79-0.99; GP:OR=1.2, 95% CI=1.05-1.38); significant at the 5% level. This study offers insight into the causal relationship between metabolites previously demonstrating association with mid-life cognition, and AD. It highlights GP in addition to several XL.HDLs as causal candidates which warrant further investigation. As the pathological changes underpinning AD are thought to develop decades prior to symptom onset, progressing these findings could hold special value in informing future risk reduction strategies.
- Downloaded 409 times
- Download rankings, all-time:
- Site-wide: 82,533
- In genetic and genomic medicine: 378
- Year to date:
- Site-wide: 60,933
- Since beginning of last month:
- Site-wide: 87,343
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!