Affiliation:
1. Department of Neurology Peking University Third Hospital Beijing China
2. Department of Neurology Ulm University Ulm Germany
3. German Center for Neurodegenerative Diseases (DZNE) Ulm Germany
4. Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases Beijing China
5. Key Laboratory for Neuroscience, National Health Commission/Ministry of Education Peking University Beijing China
6. Department of Epidemiology and Biostatistics, School of Public Health Peking University Beijing China
Abstract
AbstractObjectivePrevious observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis.MethodsUsing genome‐wide association study summary‐level data for total cholesterol (TC) (n = 188,578), high‐density lipoprotein cholesterol (HDL‐C) (n = 403,943), low‐density lipoprotein cholesterol (LDL‐C) (n = 440,546), apolipoprotein A1 (ApoA1) (n = 391,193), apolipoprotein B (ApoB) (n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL‐C is a potential mediator on the pathway from traits of LDL‐C‐related polyunsaturated fatty acids (PUFAs) to ALS risk.ResultsWe identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL‐C had the most potent effect (OR 1.028, 95% CI 1.008–1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL‐C‐modifying lifestyles and ALS. The mediation analysis revealed that LDL‐C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009.ConclusionsWe provided high‐level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL‐C in the pathway from PUFAs to ALS.
Funder
National Natural Science Foundation of China
Subject
Neurology (clinical),Neurology
Cited by
10 articles.
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