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Cited by 130Amyotrophic Lateral Sclerosis ResearchLipoproteins and Cardiovascular HealthGenetic Associations and Epidemiology

Causal effects of blood lipids on amyotrophic lateral sclerosis: a Mendelian randomization study

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Zeng, Ping, Zhou, Xiang·2019·Human Molecular Genetics
DOI 10.1093/hmg/ddy384PMC PMC6360326

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Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high-density lipoprotein, low-density lipoprotein (LDL), total cholesterol and triglycerides on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per 1 standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 [95% confidence interval (CI), 1.05-1.24; P = 1.38E-3] in the European population and 1.06 (95% CI, 1.00-1.12; P = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.

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  • Altered cholesterol, HDL and LDL metabolism, gene variants of APOA1, APOB, and APOE4, and decreased ApoA1 levels have been implicated in other neurologic disorders.

    “Altered cholesterol, HDL and LDL metabolism, gene variants of APOA1, APOB, and APOE4, and decreased ApoA1 levels have been implicated in other neurologic disorders [21–35].”

    From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [26]

    The Introduction (page unavailable) describes abnormal HDL, LDL, and total-cholesterol levels in people with ALS, and the Results (page unavailable) associate higher LDL with increased ALS risk. The paper does not establish an HDL effect or implicate APOA1, APOB, APOE4 variants, or decreased ApoA1 levels; it addresses ALS rather than neurologic disorders generally. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Zeng, P., & Zhou, X.
Affiliations
  • Xuzhou Medical College (CN)
  • University of Michigan (US)
Corresponding author
  • Zeng, Ping
  • Zhou, Xiang
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2018-11-16
Volume
28
Issue
4
Pages
688-697
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddy384
PMC
PMC6360326
OpenAlex
W2952420414
Cited by
130
References
8
Citations by year
2026: 6 · 2025: 11 · 2024: 15 · 2023: 24 · 2022: 19 · 2021: 28 · 2020: 18 · 2019: 9
FWCI
9.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Molecular Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (R01HG009124)
  • National Science Foundation (DMS1712933)
  • Natural Science Foundation of Jiangsu Province (BK20181472)
  • Youth Foundation of Humanity and Social Science funded by Ministry
  • Youth Foundation
  • Ministry of Education of China (18YJC910002)
  • China Postdoctoral Science Foundation (2018M630607)
  • Jiangsu QingLan Research Project for Outstanding Young Teachers
  • National Natural Science Foundation of China (81402765)
  • National Bureau of Statistics of China (2014LY112)
  • Priority Academic Program Development of Jiangsu Higher Education Institutions for Xuzhou Medical University
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
amyotrophic lateral sclerosis, serum lipids, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, causal risk factors, neurodegenerative diseases, modifiable risk factors
MeSH terms
Amyotrophic Lateral Sclerosis, Cholesterol, Female, Humans, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Male, Triglycerides, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis

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