Lipids and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study

Eur J Neurol. 2023 Jul;30(7):1899-1906. doi: 10.1111/ene.15810. Epub 2023 Apr 19.


Objective: Previous 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.

Methods: Using 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.

Results: We 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.

Conclusions: We 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.

Keywords: Mendelian randomization; amyotrophic lateral sclerosis; genetics; instrumental variables; lipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / epidemiology
  • Amyotrophic Lateral Sclerosis* / genetics
  • Cholesterol, LDL / genetics
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Triglycerides / genetics


  • Cholesterol, LDL
  • Triglycerides