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Testing for association between exonic glucagon-like peptide 1 receptor (GLP-1R) mutation with physical and brain health traits in UK Biobank

Ward, Joey; Lyall, Laura M; Strawbridge, Rona J; Stanciu, Ioana; Veldsman, Michele; Garfield, Victoria; Celis-Morales, Carlos; ... Lyall, Donald M; + view all (2023) Testing for association between exonic glucagon-like peptide 1 receptor (GLP-1R) mutation with physical and brain health traits in UK Biobank. Diabetes, Obesity and Metabolism: A Journal of Pharmacology and Therapeutics , 25 (2) pp. 623-627. 10.1111/dom.14879. Green open access

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Abstract

AIMS: A low-frequency exonic single nucleotide variation (SNV) in the GLP-1R gene, rs10305492, has been associated with differences in cardiometabolic health. There are well-established links between cardiometabolic and cognitive health, e.g. on neuropsychological tests, brain structure and/or risk of incident dementia. There is however a lack of data regarding rs10305492 and brain health metrics; this study aimed to test for potential associations. MATERIALS AND METHODS: We tested for association between rs10305492 A allele presence, vs. cognitive, brain imaging and dementia-related outcomes based on self-report and incident cases from hospital episode statistics, in UK Biobank (n range = 47,920 to 395,475). We controlled for covariates of age, sex, apolipoprotein (APOE) e4 genotype, 8 principal components (PCs) for population stratification, genotyping chip, and smoking history. We used linear and logistic regressions for continuous/binary outcomes (standardized betas and odds ratios [OR] respectively; A allele presence vs. absence). RESULTS: Despite significant associations with better physical health traits, there were generally no rs10305492-A associations with scores on cognitive tests, structural brain phenotype metrics or all-cause dementia, Alzheimer's disease or vascular dementia (P>0.05). There was a nominally significant protective association with lower log white matter hyperintensity volumes (standardized beta = -0.07, 95% confidence intervals = -0.13 to -0.01, P=0.028). CONCLUSION: These findings support clinical trial data in providing orthogonal, genetics-based evidence suggesting efficacy for GLP-1R agonists on physical health; but not necessarily directly for improved brain health including protection against dementia. Ongoing clinical trials are needed to provide more robust evidence. This article is protected by copyright. All rights reserved.

Type: Article
Title: Testing for association between exonic glucagon-like peptide 1 receptor (GLP-1R) mutation with physical and brain health traits in UK Biobank
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/dom.14879
Publisher version: https://doi.org/10.1111/dom.14879
Language: English
Additional information: Copyright © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License 9http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: GLP-1R, UK Biobank, cardiometabolic, dementia, imaging
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10156867
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