Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3824-3830.doi: 10.4103/NRR.NRR-D-25-00266

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Shared genetic link and causal inference between blood lipids, lipid-lowering drugs and amyotrophic lateral sclerosis

Kailin Xia1, 2, 3, #, Ninghao Huang4, #, Yajun Wang1, 2, 3, Gan Zhang1, 2, 3, Lu Tang1, 2, 3, Linjing Zhang1, 2, 3, Minhao Yao5, Zhonghua Liu5, Tao Huang4, *, Dongsheng Fan1, 2, 3, *   

  1. 1Department of Neurology, Peking University Third Hospital, Beijing, China; 
    2Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China; 
    3Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China; 
    4Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; 
    5Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong Special Administrative Region, China
  • Online:2026-08-18 Published:2026-04-28
  • Contact: Tao Huang, PhD, huangtao@bjmu.edu.cn; Dongsheng Fan, PhD, dsfan2010@aliyun.com.
  • Supported by:
    This study was funded by the National Natural Science Foundation of China, Nos. 82401670 (to KX), 81873784 (to DF), and 82071426 (to DF); the Clinical Cohort Construction Program of Peking University Third Hospital, No. BYSYDL2019002 (to DF); and the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation, No. GZC20230152 (to KX).

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Abstract: Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis, even in the presymptomatic stage, implying an etiologic link. However, the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive. Therefore, in this study, we performed genetic correlation analysis, a cross-trait meta-analysis, tissue-specific enrichment analysis, and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis. The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach. The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol, as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1. These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway. Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol. The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone. In summary, there is a common genetic structure between lipids and amyotrophic lateral sclerosis. Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis, and the use of ACLY or PCSK9 inhibitors may improve disease prognosis. 

Key words: amyotrophic lateral sclerosis, genetic correlation, genetics, instrumental variables, lipid-lowering drug, lipids, Mendelian randomization, metabolism, nerve regeneration, neurodegenerative disease, risk factor