Şanlı, B.A., Whittaker, K.J., Motsi, G.K. et al. (3 more authors) (2022) Unbiased metabolome screen links serum urate to risk of Alzheimer's disease. Neurobiology of Aging, 120. pp. 167-176. ISSN: 0197-4580
Abstract
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease caused by a combination of genetic and environmental risk factors. The serum metabolome refers to a set of small-molecules which are an important determinant of cellular health. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 376 metabolites which were population matched with 2 GWAS studies of AD. For each metabolite we performed 2-sample MR (2SMR) using an inverse variance weighted (IVW) estimate for significance testing. After Bonferroni multiple testing correction one metabolite was causally linked to AD in both GWAS: serum urate. This result was supported by robust 2SMR measures and sensitivity analyses. We applied 2SMR to test for a causal relationship between serum urate and other neurodegenerative diseases: Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS). In ALS but not PD we identified a nominally significant link between serum urate and disease-risk, although in this case increased serum urate was protective. We conclude that serum urate is a modulator of risk for neurodegeneration. Our work has implications for the design of preventative interventions.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
Keywords: | Alzheimer's Disease; Mendelian Randomization; Metabolome; Serum urate; Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Alzheimer Disease; Uric Acid; Polymorphism, Single Nucleotide; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Parkinson Disease; Metabolome |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 216596/Z/19/Z |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 29 Aug 2025 11:51 |
Last Modified: | 29 Aug 2025 11:51 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.neurobiolaging.2022.09.004 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:230764 |