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Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization

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Abstract

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, “cholesterol-lowering medication” and “atorvastatin” survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E − 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E − 4; LDLR, OR = 0.910, P = 2.73E − 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

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Availability of Data and Materials

The GWAS summary statistics supporting this research are available from the corresponding GWAS consortium. The main paper and supplementary materials present all data supporting our findings. The code or algorithm used to generate results in this study is available from the corresponding authors upon reasonable request.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

CHD:

Coronary heart disease

UKB:

UK Biobank

MRC-IEU:

Medical Research Council Integrative Epidemiology Unit

GWAS:

Genome-wide association studies

SNP:

Single nucleotide polymorphism

MR:

Mendelian randomization

IVW:

Inverse variance weighted

IV:

Instrumental variables

Q test:

Cochran’s Q test

MR-PRESSO:

MR pleiotropy residual sum and outlier

OR:

Odds ratio

CI:

Confidence interval

TG:

Triglycerides

TC:

Total cholesterol

LDL:

Low-density lipoprotein cholesterol

HDL:

High-density lipoprotein cholesterol

ApoB:

Apoprotein B

ApoA1:

Apoprotein A1

EUR:

Europeans

EAS:

East Asians

NA:

Not available

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Funding

This study was supported by the National Key Research and Development Program of China (Grant No. 2022YFC2703101 to Y.P.C), the National Natural Science Fund of China (Grant No. 82371422 and 81971188 to Y.P.C.), the National Natural Science Fund of Sichuan (Grant No. 2022NSFSC0749 to B.C.), and the Science and Technology Bureau Fund of Sichuan Province (Grant No. 2023YFS0269 to Y.P.C). We are grateful to all the studies that have made the public GWAS summary data available. We thank all the patients and their families for their generous contribution to this research.

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Authors and Affiliations

  1. Department of Neurology, Centre for Rare Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Zheng Jiang, Wei-Ming Su, Qing-Qing Duan, Kang-Fu Yin, Bei Cao & Yong-Ping Chen

  2. Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Xiao-Jing Gu

  3. Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China

    Yan-Lin Ren & Yi Wang

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  1. Zheng Jiang
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Contributions

Z.J. and Y.P.C. contributed to the conception and design of the study; Z.J., X.J.G., W.M.S., Q.Q.D., K.F.Y., Y.L.R., Y.W., and B.C. contributed to the acquisition and analysis of data; Z.J. and Y.P.C. contributed to drafting the text and preparing the figures.

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Correspondence to Yong-Ping Chen.

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Jiang, Z., Gu, XJ., Su, WM. et al. Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04007-9

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