气候变化领域集成服务门户(CCPortal): Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer's disease

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DOI	10.1073/pnas.2009808118
	Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer's disease
	Lord J.; Jermy B.; Green R.; Wong A.; Xu J.; Legido-Quigley C.; Dobson R.; Richards M.; Proitsi P.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	There are currently no disease-modifying treatments for Alzheimer's disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition-a preclinical predictor of AD-translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR-BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs-particularly XL.HDL.FC-as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	Alzheimer's disease; Biomarkers; Causality; Mendelian randomization; Metabolomics
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179794
作者单位	Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 5AF, United Kingdom; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, United Kingdom; National Institute for Health Research Maudsley Biomedical Research Centre, South London and Maudsley National Health Service (NHS) Foundation Trust, London, SE5 8AF, United Kingdom; MRC Unit for Lifelong Health and Ageing, UCL, University College London, London, WC1E 7HB, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, SE1 9NH, United Kingdom; Systems Medicine, Steno Diabetes Centre Copenhagen, Gentofte, 2820, Denmark; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, United Kingdom; National Institute for Health Re...
推荐引用方式 GB/T 7714	Lord J.,Jermy B.,Green R.,et al. Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer's disease[J],2021,118(16).
APA	Lord J..,Jermy B..,Green R..,Wong A..,Xu J..,...&Proitsi P..(2021).Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Lord J.,et al."Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer's disease".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).